Golgi Stress Response: New Insights into the Pathogenesis and Therapeutic Targets of Human Diseases

Won Kyu Kim, Wooseon Choi, Barsha Deshar, Shinwon Kang

Abstract

The Golgi apparatus modifies and transports secretory and membrane proteins. In some instances, the production of secretory and membrane proteins exceeds the capacity of the Golgi apparatus, including vesicle trafficking and the post-translational modification of macromolecules. These proteins are not modified or delivered appropriately due to the insufficiency in the Golgi function. These conditions disturb Golgi homeostasis and induce a cellular condition known as Golgi stress, causing cells to activate the ‘Golgi stress response,’ which is a homeostatic process to increase the capacity of the Golgi based on cellular requirements. Since the Golgi functions are diverse, several response pathways involving TFE3, HSP47, CREB3, proteoglycan, mucin, MAPK/ETS, and PERK regulate the capacity of each Golgi function separately. Understanding the Golgi stress response is crucial for revealing the mechanisms underlying Golgi dynamics and its effect on human health because many signaling molecules are related to diseases, ranging from viral infections to fatal neurodegenerative diseases. Therefore, it is valuable to summarize and investigate the mechanisms underlying Golgi stress response in disease pathogenesis, as they may contribute to developing novel therapeutic strategies. In this review, we investigate the perturbations and stress signaling of the Golgi, as well as the therapeutic potentials of new strategies for treating Golgi stress-associated diseases.

Keywords: Golgi stress, Golgi stress response, human disease, pathogenesis, therapeutic target

INTRODUCTION

The Golgi apparatus is involved in the intracellular transport and maturation of proteins and lipids (Rohn et al., 2000; Viotti, 2016). More than a third of all human genes are known to encode proteins that travel through the Golgi (Yuen et al., 1997). The Golgi has a distinctive structure with several layers of flat, semicircular vesicles known as cisternae. Most research has concentrated on the molecular and physiological mechanisms behind the Golgi apparatus’s structural characteristics and material transport (Duden, 2003; Klumperman, 2000; Lee et al., 2004; Tamaki and Yamashina, 2002; Watson and Stephens, 2005). Recent studies indicate that the Golgi functions as a signaling hub in intracellular signal transduction pathways involved in the development and progression of many diseases (Cancino and Luini, 2013; Makhoul et al., 2019; Spano and Colanzi, 2022). The pathophysiological involvement of the Golgi is attracting interest because protein quality control, which is known to have a significant association with the pathogenesis of numerous diseases, is associated with the Golgi (Schwabl and Teis, 2022).

Pathophysiological cellular stress stimuli affect Golgi homeostasis directly (Li et al., 2019; Liu et al., 2021), resulting in Golgi stress. In response to Golgi stress, cells activate adaptive mechanisms to overcome the stress and restore Golgi homeostasis. Although Golgi stress is not as well established as endoplasmic reticulum (ER) stress, increasing evidence indicates that distinct signaling cascades are involved in the Golgi stress response. This review highlights the potential triggers of Golgi stress, related signaling mechanisms, and therapeutic strategies that target Golgi stress signaling.

FACTORS DISRUPTING FUNCTIONAL AND MORPHOLOGICAL INTEGRITY/HOMEOSTASIS OF THE GOLGI APPARATUS

Molecular-level factors

Several small compounds that trigger Golgi stress via various mechanisms have been discovered. Stressors include monensin (Boss et al., 1984; Ellinger and Pavelka, 1984) and nigericin (Suga et al., 2015), which are ionophores that neutralize luminal pH and block intra-Golgi trafficking, and lithocholylglycine, which inhibits α-2,3-sialyltransferase activity (Chang et al., 2006). Targeting the ADP ribosylation factor (ARF) proteins with compounds, such as Brefeldin A (Robineau et al., 2000) and Golgicide A (Saenz et al., 2009), induces Golgi stress by increasing redistribution of the Golgi in the ER. Exo2 prevents the anterograde movement of the viral glycoprotein VSVG (vesicular stomatitis virus G) from the ER to the Golgi, resulting in a selective disruption of the Golgi without affecting the trans-Golgi network (TGN) (Feng et al., 2004). Also, DNA damage induced by chemotherapeutic agents, such as camptothecin and doxorubicin, triggers Golgi fragmentation and inhibits vesicular transport via DNA-PK-mediated GOLPH3 phosphorylation (Farber-Katz et al., 2014).

Contextual factors

Numerous cancer cell lines, including breast (Sewell et al., 2006), colon (Kellokumpu et al., 2002), and prostate cancer cells (Nolfi et al., 2020), exhibit fragmented Golgi. The structural and functional changes in the Golgi contribute to the survival, proliferation, and metastasis of cancer cells (Bui et al., 2021; Petrosyan, 2015). The uncontrolled proliferation of cancer cells requires massive protein synthesis, which impacts the Golgi’s regulation of the cancer cell secretome (Bajaj et al., 2022). Cancer-induced perturbations of the Golgi can evoke intrinsic signals to alter Golgi architecture and trafficking kinetics (Howley and Howe, 2018).

In addition, cancer cells and microenvironments conducive to tumor growth are essential components of both primary and secondary tumors (Baghban et al., 2020). Golgi perturbation is induced by microenvironmental stressors, including acidification, hypoxia, and nutritional deprivation (Bui et al., 2021). Interrupting glycosylation, nutrient deficiency, and especially glucose deficiency contribute to Golgi stress. The functional alterations of Golgi have also been associated with neurodegenerative diseases such as Huntington’s disease (Sbodio et al., 2018), amyotrophic lateral sclerosis (Park et al., 2020) and Alzheimer’s disease (Suga et al., 2022), and metabolic diseases such as diabetes (Bone et al., 2020) and lipotoxicity (Bascil Tutuncu et al., 2022).

CELLULAR RESPONSE TO GOLGI STRESS

In response to Golgi stress, cells activate an adaptive signaling pathway known as the Golgi stress response, which assists cells in coping with the stress by enhancing the capacity of the Golgi for maturation and secretion of proteins and clearing the accumulation of proteins within the Golgi.

Recent research has shed light on a critical component of the regulatory mechanism underlying the Golgi stress response. This component includes transcription factor binding to IGHM enhancer 3 (TFE3), CAMP Responsive Element Binding Protein 3 (CREB3), mitogen-activated protein kinases/erythroblast transformation specific (MAPK/ETS), the protein kinase R (PKR)-like ER kinase (PERK), proteoglycan, mucin, and heat shock protein 47 (HSP47) pathways (Fig. 1). TFE3 is a transcription factor that acts as a master regulator of lysosomal biogenesis and immune response (Beckmann et al., 1990; Lawrence et al., 2019; Mathieu et al., 2019; Willett et al., 2017). It has been reported that Golgi stress-mediated dephosphorylated TFE3 binds a Golgi apparatus stress response element (GASE) to activate the transcription of Golgi-associated genes, including glycosylation enzymes (fucosyltransferase 1, sialyltransferase 4A, sialyltransferase 10, and UDP-N-acetylhexosamine pyrophosphorylase-like 1), Golgi structural proteins (GM130, Giantin, and GCP60), and vesicular transport components (RAB20, STX 3A, and WIPI49) (Oku et al., 2011; Taniguchi et al., 2015). Treating cells with Brefeldin A activates the CREB3-ARF4 pathway and inhibits the function of ARF proteins. Consequently, the cytoplasmic domains of CREB3 are released from the ER membrane and translocated into the nucleus to upregulate the Golgi-associated genes, including ARF4, resulting in Golgi stress-induced apoptosis (Howley et al., 2018; Reiling et al., 2013).

Figure 1

Golgi stress response pathway.Golgi stress-induced dephosphorylation of TFE3 promotes the transcription of target genes via GASE. Insufficient glycosylation of mucin and proteoglycans activate Golgi stress response through MGSE-mediated activation of ...

MAPK and PERK pathways involve the enzyme-mediated cascade in response to Golgi stress. The MAPK cascade and ETS family transcription factor induce apoptosis under Golgi stress (Baumann et al., 2018). PERK, a protein kinase that belongs to the eIF2α kinase subfamily, activated upon ER stress, has been identified as a pathway activated by the Golgi stressor monensin (Sbodio et al., 2018). Interestingly, PERK-mediated Golgi stress response acts via the eIF2α/ATF4/AARE (amino acid response elements) but is independent of the ER-resident chaperone BiP/GRP78, suggesting that this pathway is a distinct type of stress response. In addition, although transcription factors have not been identified, certain signaling pathways are known to contribute to the Golgi stress response. For example, the proteoglycan pathway is activated in case of insufficient proteoglycan glycosylation in the Golgi. It upregulates the transcription of genes encoding glycosyltransferase and sulfotransferase through an enhancer known as proteoglycan-type Golgi stress response element (PGSE) (Sasaki et al., 2019). Mucins are highly glycosylated, viscous proteins, and inadequate glycosylation of mucins induces a mucin-type Golgi stress response accompanied by TFE3 activation via mucin-type Golgi stress response element (MGSE) (Jamaludin et al., 2019). HSP47 is an ER chaperone, and its upregulation in response to Golgi stress protects cells against apoptosis (Miyata et al., 2013).

Notably, it has been recently reported that the Golgi stress response participates in protein homeostasis through three Golgi-associated degradation signaling pathways: Golgi apparatus-related degradation (GARD), endosome and Golgi-related stress-responsive associated degradation (EGAD), and Golgi membrane-associated degradation (GOMED).

Golgi stress changes Golgi morphology via proteasome-mediated degradation of the Golgi tethering factor GM130 bound to the cytosolic side of the Golgi membrane (Eisenberg-Lerner et al., 2020). This process, known as GARD, enables the Golgi to rapidly adjust its structure via localized proteasomal degradation in response to stress. In addition, GARD may be associated with the pathogenesis of virus infection. For example, herpes simplex virus has been reported to downregulate GM130 and induce Golgi fragmentation (He et al., 2020). It remains to be determined whether GARD-dependent regulation of Golgi stress is a feature of viral infection accompanied by Golgi fragmentation.

In EGAD, Golgi membrane proteins are degraded by Golgi and cytosolic proteasomes without returning to the ER (Schmidt et al., 2019). An example of EGAD is Orm2, the Golgi membrane protein in budding yeast. Orm2 is a conserved subunit of the serine:palmitoyl-coenzyme. It is a transferase complex that negatively regulates the production of sphingolipids (Hannun and Obeid, 2018). Orm2 is polyubiquitinated by the Golgi-localized Dsc E3 ligase complex, separated from the membrane by the ATPase VCP/CDC48, and subsequently degraded by cytosolic proteasomes, in contrast to most Golgi-polyubiquitinated proteins, which are sorted by the endosomal sorting complex required for transport (ESCRT) components for vacuolar/lysosomal degradation (Schmidt et al., 2019). It is possible that EGAD-dependent proteasomal degradation of Orm2 functions as the post-ER checkpoint to regulate lipid metabolism in budding yeast.

While GARD and EGAD contribute to proteostasis by using the proteasome system, GOMED is a distinct mechanism that degrades Golgi trafficking proteins via trans-Golgi membranes (Noguchi and Shimizu, 2022). When Golgi trafficking is disrupted, the trans-Golgi membrane invaginates and engulfs proteins that could not be secreted or delivered to the plasma membranes, causing them to be accumulated in the TGN as degrading cargos; this process is also known as ATG5/ATG7-independent alternative autophagy (Nishida et al., 2009). WIPI3, a polyphosphoinositide-binding protein, has been recently reported as a key regulator of GOMED that binds to the Golgi membrane to form autophagosome-like structures (Yamaguchi et al., 2020). WIPI3-mediated alternative autophagy is required to maintain neuronal cells via a mechanism different from ATG-dependent canonical autophagy.

In Golgi stress response research, an unsettled but essential question is: what are the properties of molecules that sense Golgi stress and initiate signaling? Sensors for each pathway of Golgi stress response have not been elucidated. However, several candidates have recently been suggested. For example, it has been reported that GOLPH3, a peripheral membrane protein localized to the Golgi, is not only a Golgi stress sensor but also an initiator that transmits Golgi stress signals to the downstream pathway (Li et al., 2016). ATG9A/MARCH9/GRASP55 has been suggested as a direct sensor of heat-induced Golgi stress (Luo et al., 2022). Identifying common or individual sensors for these seven pathways would be essential for characterizing the Golgi stress response.

GOLGI STRESS IN DISEASES

Recent findings of Golgi stress signaling in human diseases

Recent research has uncovered new Golgi stress-mediated regulators and mechanisms involved in the infections and immune responses caused by pathogens such as viruses, bacteria, and parasites. For example, Influenza A virus infection leads to TGN dispersion, which depends on the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation (Pandey and Zhou, 2022). TGN serves as a platform for the recruitment of NLRP3 and its downstream adaptor proteins, resulting in the formation of an active inflammasome. Interestingly, it has been reported that the Golgi stressor nigericin induces NLRP3 aggregation on dispersed TGN (Chen and Chen, 2018). This implies that Golgi fragmentation-induced Golgi stress constitutes an antiviral host defense by facilitating aggregation of NLRP3 inflammasome. Like the Influenza A virus, host cells infected by Shigella bacteria upregulate SIRT2, a potent lysine defatty-acylase, which is upregulated via the CREB3-mediated Golgi stress response (Wang et al., 2022). SIRT2 then removes the lysine fatty acylation that was introduced by Shigella virulence factor IcsB to boost the innate immunity of the host, suggesting the importance of SIRT2 in counteracting Shigella infection. In contrast to Shigella, a genome-wide CRISPR-Cas9 screen revealed that Plasmodium parasites, surprisingly, utilized Golgi stress during host infection (Vijayan et al., 2022). Knock-out of centromere protein J (CENPJ), a centrosomal MT organizing complex (MTOC) protein, enhances the efficiency of Plasmodium infection. This suggests that the parasite relies on non-centrosomal MT (Vijayan et al., 2022). Considering that the host Golgi acts as a non-centrosomal MTOC (ncMTOC) at the parasite periphery and Golgi-mediated MTOC repositioning regulates host vesicular trafficking to the parasite (De Niz et al., 2021; Romano et al., 2013; Zhu and Kaverina, 2013), the investigation of the involvement of ncMTOCs in the Golgi stress response would provide new insights into not only Golgi stress signaling but also novel mechanisms of parasite-host interactions.

In non-small cell lung cancer (NSCLC), cellular retinoic acid binding protein 2 (CRABP2) is involved in PERK/ATF4-mediated Golgi stress (Meng and Luo, 2021). CRABP2 was initially identified as a regulator of retinoic acid signal transduction (Zhang et al., 2019). However, high CRABP2 levels correlate with poor prognoses, such as poor overall survival, increased recurrence, and advanced lymph node metastasis, in NSCLC patients (Wu et al., 2019). This implies that CRABP2-associated Golgi stress is involved in metastatic lung cancer via the PERK pathway.

Notably, it has been linked to the neurotoxic effects of Golgi stress (Suga et al., 2022). Golgi stress induced by several compounds such as monensin, nigericin, Exo2, and golgicide A increases the expression of ER-Golgi SNARE Syntaxin5 isoforms, decreases βAPP processing, and consequently, increases the accumulation of β-amyloid. However, when Golgi stress continues, caspase-3 is activated, leading to neuronal cell death. The Golgi stress-induced PERK pathway also contributes to Huntington’s disease (Sbodio et al., 2018). However, mild-Golgi stress may have a cytoprotective role via the PERK pathway in Huntington’s disease. These results suggest that the Golgi stress response, like other stress responses, acts as a defense mechanism that allows cells to adapt or overcome stress under short and moderate stress conditions but acts as an aggravating factor that causes disease under strong and continuous stress conditions.

Potential therapeutic targets of the Golgi stress in human diseases

To improve the therapeutic index of a drug, it is most desirable to deliver the therapeutic molecule in its active form to the intracellular therapeutic active site of the targeted organelle (Sakhrani and Padh, 2013). Strategies are being actively developed to improve efficacy and minimize the toxicity of drug treatment for targeting organelles, especially for the Golgi. For example, chondroitin sulfate-based prodrug nanoparticles have been recently developed to target the Golgi in tumor cells. They reduce photodynamic immunotherapy-mediated immunosuppression by blocking the production of immunosuppressive cytokines (Li et al., 2022a).

The development of Golgi stress response-targeting therapeutics is a promising research area (Table 1). Results from previous studies have provided novel mechanistic insights to modulate Golgi stress response in diseases. For example, a low concentration of monensin prevents the toxicity associated with cysteine deprivation in Huntington’s disease by upregulating the reverse transsulfuration pathway by PERK-mediated Golgi stress response and its targets, including cystathionine γ-lyase (Sbodio et al., 2018). This reveals that low-grade Golgi stress, which does not result in toxicity, can upregulate cytoprotective defensive systems and may prime or precondition cells to survive subsequent stresses. Therefore, rather than completely suppressing the Golgi stress response, balancing it at an appropriate level would be beneficial for treating Huntington’s disease.

It is also possible that Golgi-associated degradation pathways such as GARD, EGAD, and GOMED are involved in proteinopathies, which have an archetypal feature of protein misfolding and accumulated structures (Bayer, 2015). The clearance of the proteins is essential for maintaining cell integrity (Bae et al., 2012; Deleidi and Maetzler, 2012). For example, the brain could be damaged by the dysfunction of protein clearance including unfolded protein response, autophagy, and phagocytosis (Alvarez-Erviti et al., 2010; Chiti and Dobson, 2017; Hartl, 2017; Kumar et al., 2016). Theoretically, enhancing the clearance capacity of the proteins via the Golgi stress-induced degradation pathway would provide a novel approach to treating proteinopathies including neurodegenerative diseases.

CONCLUSION AND PERSPECTIVES

The Golgi research area has focused on the structure and function of the Golgi or Golgi proteins. However, only a few studies exist on Golgi stress-associated pathogenesis. The extent and significance of the Golgi stress response are not entirely known. This is primarily due to a lack of reliable and precise experimental approaches specific to the Golgi. However, Golgi-specific experimental methods, particularly imaging techniques, are being actively developed. Gol_ROS has been developed as a fluorescence probe for O₂^- and H₂O₂ in the Golgi (Wang et al., 2019). It could quantitatively measure the Golgi reactive oxygen species and the pharmacological effect of antihypertensive drugs. In addition to Gol_ROS, several other Golgi-targeted probes have been developed. Golgi-NO has been developed as the Golgi-targeted fluorescent probe for visualizing nitric oxide (NO) in the Golgi (He et al., 2022). NO is a crucial neurotransmitter involved in various diseases, including Alzheimer’s disease. This novel Golgi-targeted probe would be used as a tool for investigating the dysfunctional role of nitrosylation. Gol-NCS, an isothiocyanate-based Golgi-targeting fluorescent probe for cysteine (Cys), has been developed to detect the fluctuation of Cys content of Golgi and monitor the production of endogenous Cys during Golgi stress (Zhu et al., 2022). Golgi-Nap-CORM-3 is a Golgi-targetable fluorescent probe that detects carbon monoxide (CO)-releasing molecule-3 (CORM-3). It consists mainly of metal carbonyl compounds and is used as an experimental tool to deliver CO (Li et al., 2022b). Many different fluorescent probes have been developed that specifically target the Golgi, and they may prove helpful in advancing our understanding of the diseases associated with Golgi stress.

Insights from the above aspects will facilitate the understanding of why Golgi stress is induced via different pathways and how distinct Golgi stress signaling pathways are implicated in human diseases. To modulate the Golgi stress response with a therapeutic potential for various diseases, the characterization of the signaling pathways induced by the Golgi stress, the various substrates, and their regulatory processes is paramount. Golgi stress response is an active research area with many challenging questions. A comprehensive understating of the Golgi stress response will provide a complete view of the role of Golgi-associated pathogenesis in diseases, including diabetes, infectious diseases, inflammatory diseases, cancer, and neurodegenerative diseases

Article information

Mol. Cells.Apr 30, 2023; 46(4): 191-199.

Published online 2022-12-28. doi: 10.14348/molcells.2023.2152

Won Kyu Kim, Wooseon Choi, Barsha Deshar, Shinwon Kang

¹Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea

²Division of Bio-Medical Science & Technology, University of Science and Technology (UST), Daejeon 34113, Korea

³Department of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea

⁴Department of Physiology, University of Toronto, Toronto, ON M5S, Canada

⁵Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON M5G, Canada

^*Correspondence: jykim@catholic.ac.kr

Received September 27, 2022; Accepted October 30, 2022.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

Articles from Mol. Cells are provided here courtesy of Mol. Cells

References

Alborzinia, H., Ignashkova, T.I., Dejure, F.R., Gendarme, M., Theobald, J., Wölfl, S., Lindemann, R.K., Reiling, J.H. (2018). Golgi stress mediates redox imbalance and ferroptosis in human cells. Commun. Biol.. 1, 210.
Alvarez-Erviti, L., Rodriguez-Oroz, M.C., Cooper, J.M., Caballero, C., Ferrer, I., Obeso, J.A., Schapira, A.H. (2010). Chaperone-mediated autophagy markers in Parkinson disease brains. Arch. Neurol.. 67, 1464-1472.
Bae, E.J., Lee, H.J., Rockenstein, E., Ho, D.H., Park, E.B., Yang, N.Y., Desplats, P., Masliah, E., Lee, S.J. (2012). Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci.. 32, 13454-13469.
Baghban, R., Roshangar, L., Jahanban-Esfahlan, R., Seidi, K., Ebrahimi-Kalan, A., Jaymand, M., Kolahian, S., Javaheri, T., Zare, P. (2020). Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun. Signal.. 18, 59.
Bajaj, R., Warner, A.N., Fradette, J.F., Gibbons, D.L. (2022). Dance of the Golgi: understanding Golgi dynamics in cancer metastasis. Cells. 11, 1484.
Bascil Tutuncu, N., Verdi, H., Yalcin, Y., Baysan Cebi, P., Kinik, S., Tutuncu, T., Atac, F.B. (2022). Beta-cell Golgi stress response to lipotoxicity and glucolipotoxicity: a preliminary study of a potential mechanism of beta-cell failure in posttransplant diabetes and intraportal islet transplant. Exp. Clin. Transplant.. 20, 585-594.
Baumann, J., Ignashkova, T.I., Chirasani, S.R., Ramirez-Peinado, S., Alborzinia, H., Gendarme, M., Kuhnigk, K., Kramer, V., Lindemann, R.K., Reiling, J.H. (2018). Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing. Mol. Biol. Cell. 29, 42-52.
Bayer, T.A. (2015). Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?. Eur. Neuropsychopharmacol.. 25, 713-724.
Beckmann, H., Su, L.K., Kadesch, T. (1990). TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev.. 4, 167-179.
Bone, R.N., Oyebamiji, O., Talware, S., Selvaraj, S., Krishnan, P., Syed, F., Wu, H., Evans-Molina, C. (2020). A computational approach for defining a signature of beta-cell Golgi stress in diabetes. Diabetes. 69, 2364-2376.
Boss, W.F., Morre, D.J., Mollenhauer, H.H. (1984). Monensin-induced swelling of Golgi apparatus cisternae mediated by a proton gradient. Eur. J. Cell Biol.. 34, 1-8.
Bui, S., Mejia, I., Diaz, B., Wang, Y. (2021). Adaptation of the Golgi apparatus in cancer cell invasion and metastasis. Front. Cell Dev. Biol.. 9, 806482.
Cancino, J., Luini, A. (2013). Signaling circuits on the Golgi complex. Traffic. 14, 121-134.
Chang, K.H., Lee, L., Chen, J., Li, W.S. (2006). Lithocholic acid analogues, new and potent alpha-2,3-sialyltransferase inhibitors. Chem. Commun. (Camb.). , 629-631.
Chen, J., Chen, Z.J. (2018). PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature. 564, 71-76.
Chiti, F., Dobson, C.M. (2017). Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu. Rev. Biochem.. 86, 27-68.
De Niz, M., Caldelari, R., Kaiser, G., Zuber, B., Heo, W.D., Heussler, V.T., Agop-Nersesian, C. (2021). Hijacking of the host cell Golgi by Plasmodium berghei liver stage parasites. J. Cell Sci.. 134, jcs252213.
Deleidi, M., Maetzler, W. (2012). Protein clearance mechanisms of alpha-synuclein and amyloid-Beta in lewy body disorders. Int. J. Alzheimers Dis.. 2012, 391438.
Deng, S., Hu, Q., Chen, X., Lei, Q., Lu, W. (2022). GM130 protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by regulating autophagy formation. Exp. Gerontol.. 163, 111772.
Duden, R. (2003). ER-to-Golgi transport: COP I and COP II function (Review). Mol. Membr. Biol.. 20, 197-207.
Eisenberg-Lerner, A., Benyair, R., Hizkiahou, N., Nudel, N., Maor, R., Kramer, M.P., Shmueli, M.D., Zigdon, I., Cherniavsky Lev, M., Ulman, A. (2020). Golgi organization is regulated by proteasomal degradation. Nat. Commun.. 11, 409.
Ellinger, A., Pavelka, M. (1984). Effect of monensin on the Golgi apparatus of absorptive cells in the small intestine of the rat. Morphological and cytochemical studies. Cell Tissue Res.. 235, 187-194.
Farber-Katz, S.E., Dippold, H.C., Buschman, M.D., Peterman, M.C., Xing, M., Noakes, C.J., Tat, J., Ng, M.M., Rahajeng, J., Cowan, D.M. (2014). DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3. Cell. 156, 413-427.
Feng, Y., Jadhav, A.P., Rodighiero, C., Fujinaga, Y., Kirchhausen, T., Lencer, W.I. (2004). Retrograde transport of cholera toxin from the plasma membrane to the endoplasmic reticulum requires the trans-Golgi network but not the Golgi apparatus in Exo2-treated cells. EMBO Rep.. 5, 596-601.
Hannun, Y.A., Obeid, L.M. (2018). Sphingolipids and their metabolism in physiology and disease. Nat. Rev. Mol. Cell Biol.. 19, 175-191.
Hartl, F.U. (2017). Protein misfolding diseases. Annu. Rev. Biochem.. 86, 21-26.
He, Q., Liu, H., Huang, C., Wang, R., Luo, M., Lu, W. (2020). Herpes simplex virus 1-induced blood-brain barrier damage involves apoptosis associated with GM130-mediated Golgi stress. Front. Mol. Neurosci.. 13, 2.
He, Z., Liu, D., Liu, Y., Li, X., Shi, W., Ma, H. (2022). Golgi-targeted fluorescent probe for imaging NO in Alzheimer's disease. Anal. Chem.. 94, 10256-10262.
Howley, B.V., Howe, P.H. (2018). Metastasis-associated upregulation of ER-Golgi trafficking kinetics: regulation of cancer progression via the Golgi apparatus. Oncoscience. 5, 142-143.
Howley, B.V., Link, L.A., Grelet, S., El-Sabban, M., Howe, P.H. (2018). A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer. Oncogene. 37, 1308-1325.
Jamaludin, M.I., Wakabayashi, S., Taniguchi, M., Sasaki, K., Komori, R., Kawamura, H., Takase, H., Sakamoto, M., Yoshida, H. (2019). MGSE regulates crosstalk from the mucin pathway to the TFE3 pathway of the Golgi stress response. Cell Struct. Funct.. 44, 137-151.
Kellokumpu, S., Sormunen, R., Kellokumpu, I. (2002). Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra-Golgi pH. FEBS Lett.. 516, 217-224.
Klumperman, J. (2000). Transport between ER and Golgi. Curr. Opin. Cell Biol.. 12, 445-449.
Kumar, V., Sami, N., Kashav, T., Islam, A., Ahmad, F., Hassan, M.I. (2016). Protein aggregation and neurodegenerative diseases: from theory to therapy. Eur. J. Med. Chem.. 124, 1105-1120.
Lawrence, R.E., Fromm, S.A., Fu, Y., Yokom, A.L., Kim, D.J., Thelen, A.M., Young, L.N., Lim, C.Y., Samelson, A.J., Hurley, J.H. (2019). Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 366, 971-977.
Lee, M.C., Miller, E.A., Goldberg, J., Orci, L., Schekman, R. (2004). Bi-directional protein transport between the ER and Golgi. Annu. Rev. Cell Dev. Biol.. 20, 87-123.
Li, H., Deng, C., Tan, Y., Dong, J., Zhao, Y., Wang, X., Yang, X., Luo, J., Gao, H., Huang, Y. (2022a). Chondroitin sulfate-based prodrug nanoparticles enhance photodynamic immunotherapy via Golgi apparatus targeting. Acta Biomater.. 146, 357-369.
Li, J., Ahat, E., Wang, Y. (2019). Golgi structure and function in health, stress, and diseases. Results Probl. Cell Differ.. 67, 441-485.
Li, S., Yang, K., Zeng, J., Ding, Y., Cheng, D., He, L. (2022b). Golgi-targeting fluorescent probe for monitoring CO-releasing molecule-3 in vitro and in vivo. ACS Omega. 7, 9929-9935.
Li, T., You, H., Mo, X., He, W., Tang, X., Jiang, Z., Chen, S., Chen, Y., Zhang, J., Hu, Z. (2016). GOLPH3 mediated Golgi stress response in modulating N2A cell death upon oxygen-glucose deprivation and reoxygenation injury. Mol. Neurobiol.. 53, 1377-1385.
Li, X., Yu, J., Gong, L., Zhang, Y., Dong, S., Shi, J., Li, C., Li, Y., Zhang, Y., Li, H. (2021). Heme oxygenase-1(HO-1) regulates Golgi stress and attenuates endotoxin-induced acute lung injury through hypoxia inducible factor-1α (HIF-1α)/HO-1 signaling pathway. Free Radic. Biol. Med.. 165, 243-253.
Liu, J., Huang, Y., Li, T., Jiang, Z., Zeng, L., Hu, Z. (2021). The role of the Golgi apparatus in disease (Review). Int. J. Mol. Med.. 47, 38.
Luo, Q., Liu, Q., Cheng, H., Wang, J., Zhao, T., Zhang, J., Mu, C., Meng, Y., Chen, L., Zhou, C. (2022). Nondegradable ubiquitinated ATG9A organizes Golgi integrity and dynamics upon stresses. Cell Rep.. 40, 111195.
Makhoul, C., Gosavi, P., Gleeson, P.A. (2019). Golgi dynamics: the morphology of the mammalian Golgi apparatus in health and disease. Front. Cell Dev. Biol.. 7, 112.
Mathieu, J., Detraux, D., Kuppers, D., Wang, Y., Cavanaugh, C., Sidhu, S., Levy, S., Robitaille, A.M., Ferreccio, A., Bottorff, T. (2019). Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency. Nat. Commun.. 10, 632.
Meng, J.F., Luo, M.J. (2021). CRABP2 involvement in a mechanism of Golgi stress and tumor dry matter in non-small cell lung cancer cells via ER dependent Hippo pathway. Acta Biochim. Pol.. 69, 31-36.
Miyata, S., Mizuno, T., Koyama, Y., Katayama, T., Tohyama, M. (2013). The endoplasmic reticulum-resident chaperone heat shock protein 47 protects the Golgi apparatus from the effects of O-glycosylation inhibition. PLoS One. 8, e69732.
Mytych, J., Sołek, P., Będzińska, A., Rusinek, K., Warzybok, A., Tabęcka-Łonczyńska, A., Koziorowski, M. (2020). Towards age-related anti-inflammatory therapy: klotho suppresses activation of ER and Golgi stress response in senescent monocytes. Cells. 9, 261.
Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T., Komatsu, M., Otsu, K., Tsujimoto, Y., Shimizu, S. (2009). Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature. 461, 654-658.
Noguchi, S., Shimizu, S. (2022). Molecular mechanisms and biological roles of GOMED. FEBS J.. 289, 7213-7220.
Nolfi, D., Capone, A., Rosati, F., Della Giovampaola, C. (2020). The alpha-1,2 fucosylated tubule system of DU145 prostate cancer cells is derived from a partially fragmented Golgi complex and its formation is actin-dependent. Exp. Cell Res.. 396, 112324.
Ochiai, A., Sawaguchi, S., Memezawa, S., Seki, Y., Morimoto, T., Oizumi, H., Ohbuchi, K., Yamamoto, M., Mizoguchi, K., Miyamoto, Y. (2022). Knockdown of Golgi stress-responsive caspase-2 ameliorates HLD17-associated AIMP2 mutant-mediated inhibition of oligodendroglial cell morphological differentiation. Neurochem. Res.. 47, 2617-2631.
Oku, M., Tanakura, S., Uemura, A., Sohda, M., Misumi, Y., Taniguchi, M., Wakabayashi, S., Yoshida, H. (2011). Novel cis-acting element GASE regulates transcriptional induction by the Golgi stress response. Cell Struct. Funct.. 36, 1-12.
Pandey, K.P., Zhou, Y. (2022). Influenza A virus infection activates NLRP3 inflammasome through trans-Golgi network dispersion. Viruses. 14, 88.
Park, J.H., Chung, C.G., Seo, J., Lee, B.H., Lee, Y.S., Kweon, J.H., Lee, S.B. (2020). C9orf72-associated arginine-rich dipeptide repeat proteins reduce the number of Golgi outposts and dendritic branches in Drosophila neurons. Mol. Cells. 43, 821-830.
Petrosyan, A. (2015). Onco-Golgi: is fragmentation a gate to cancer progression?. Biochem. Mol. Biol. J.. 1, 16.
Reiling, J.H., Olive, A.J., Sanyal, S., Carette, J.E., Brummelkamp, T.R., Ploegh, H.L., Starnbach, M.N., Sabatini, D.M. (2013). A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens. Nat. Cell Biol.. 15, 1473-1485.
Robineau, S., Chabre, M., Antonny, B. (2000). Binding site of brefeldin A at the interface between the small G protein ADP-ribosylation factor 1 (ARF1) and the nucleotide-exchange factor Sec7 domain. Proc. Natl. Acad. Sci. U. S. A.. 97, 9913-9918.
Rohn, W.M., Rouille, Y., Waguri, S., Hoflack, B. (2000). Bi-directional trafficking between the trans-Golgi network and the endosomal/lysosomal system. J. Cell Sci.. 113, 2093-2101.
Romano, J.D., Sonda, S., Bergbower, E., Smith, M.E., Coppens, I. (2013). Toxoplasma gondii salvages sphingolipids from the host Golgi through the rerouting of selected Rab vesicles to the parasitophorous vacuole. Mol. Biol. Cell. 24, 1974-1995.
Saenz, J.B., Sun, W.J., Chang, J.W., Li, J., Bursulaya, B., Gray, N.S., Haslam, D.B. (2009). Golgicide A reveals essential roles for GBF1 in Golgi assembly and function. Nat. Chem. Biol.. 5, 157-165.
Sakhrani, N.M., Padh, H. (2013). Organelle targeting: third level of drug targeting. Drug Des. Devel. Ther.. 7, 585-599.
Sasaki, K., Komori, R., Taniguchi, M., Shimaoka, A., Midori, S., Yamamoto, M., Okuda, C., Tanaka, R., Sakamoto, M., Wakabayashi, S. (2019). PGSE is a novel enhancer regulating the proteoglycan pathway of the mammalian Golgi stress response. Cell Struct. Funct.. 44, 1-19.
Sbodio, J.I., Snyder, S.H., Paul, B.D. (2018). Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington's disease. Proc. Natl. Acad. Sci. U. S. A.. 115, 780-785.
Schmidt, O., Weyer, Y., Baumann, V., Widerin, M.A., Eising, S., Angelova, M., Schleiffer, A., Kremser, L., Lindner, H., Peter, M. (2019). Endosome and Golgi-associated degradation (EGAD) of membrane proteins regulates sphingolipid metabolism. EMBO J.. 38, e101433.
Schwabl, S., Teis, D. (2022). Protein quality control at the Golgi. Curr. Opin. Cell Biol.. 75, 102074.
Sewell, R., Backstrom, M., Dalziel, M., Gschmeissner, S., Karlsson, H., Noll, T., Gatgens, J., Clausen, H., Hansson, G.C., Burchell, J. (2006). The ST6GalNAc-I sialyltransferase localizes throughout the Golgi and is responsible for the synthesis of the tumor-associated sialyl-Tn O-glycan in human breast cancer. J. Biol. Chem.. 281, 3586-3594.
Spano, D., Colanzi, A. (2022). Golgi Complex: a signaling hub in cancer. Cells. 11, 1990.
Suga, K., Saito, A., Mishima, T., Akagawa, K. (2015). Data for the effects of ER and Golgi stresses on the ER-Golgi SNARE Syntaxin5 expression and on the betaAPP processing in cultured hippocampal neurons. Data Brief. 5, 114-123.
Suga, K., Yamamoto-Hijikata, S., Terao, Y., Akagawa, K., Ushimaru, M. (2022). Golgi stress induces upregulation of the ER-Golgi SNARE Syntaxin-5, altered betaAPP processing, and Caspase-3-dependent apoptosis in NG108-15 cells. Mol. Cell. Neurosci.. 121, 103754.
Tamaki, H., Yamashina, S. (2002). The stack of the golgi apparatus. Arch. Histol. Cytol.. 65, 209-218.
Taniguchi, M., Nadanaka, S., Tanakura, S., Sawaguchi, S., Midori, S., Kawai, Y., Yamaguchi, S., Shimada, Y., Nakamura, Y., Matsumura, Y. (2015). TFE3 is a bHLH-ZIP-type transcription factor that regulates the mammalian Golgi stress response. Cell Struct. Funct.. 40, 13-30.
Vijayan, K., Arang, N., Wei, L., Morrison, R., Geiger, R., Parks, K.R., Lewis, A.J., Mast, F.D., Douglass, A.N., Kain, H.S. (2022). A genome-wide CRISPR-Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization during Plasmodium liver infection. Cell Chem. Biol.. 29, 1419-1433.e5.
Viotti, C. (2016). ER to Golgi-dependent protein secretion: the conventional pathway. Methods Mol. Biol.. 1459, 3-29.
Wang, H., He, Z., Yang, Y., Zhang, J., Zhang, W., Zhang, W., Li, P., Tang, B. (2019). Ratiometric fluorescence imaging of Golgi H2O2 reveals a correlation between Golgi oxidative stress and hypertension. Chem. Sci.. 10, 10876-10880.
Wang, M., Zhang, Y., Komaniecki, G.P., Lu, X., Cao, J., Zhang, M., Yu, T., Hou, D., Spiegelman, N.A., Yang, M. (2022). Golgi stress induces SIRT2 to counteract Shigella infection via defatty-acylation. Nat. Commun.. 13, 4494.
Watson, P., Stephens, D.J. (2005). ER-to-Golgi transport: form and formation of vesicular and tubular carriers. Biochim. Biophys. Acta. 1744, 304-315.
Willett, R., Martina, J.A., Zewe, J.P., Wills, R., Hammond, G.R.V., Puertollano, R. (2017). TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. Nat. Commun.. 8, 1580.
Wu, J.I., Lin, Y.P., Tseng, C.W., Chen, H.J., Wang, L.H. (2019). Crabp2 promotes metastasis of lung cancer cells via HuR and integrin beta1/FAK/ERK signaling. Sci. Rep.. 9, 845.
Yamaguchi, H., Arakawa, S., Kanaseki, T., Miyatsuka, T., Fujitani, Y., Watada, H., Tsujimoto, Y., Shimizu, S. (2016). Golgi membrane-associated degradation pathway in yeast and mammals. EMBO J.. 35, 1991-2007.
Yamaguchi, H., Honda, S., Torii, S., Shimizu, K., Katoh, K., Miyake, K., Miyake, N., Fujikake, N., Sakurai, H.T., Arakawa, S. (2020). Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration. Nat. Commun.. 11, 5311.
Yuen, C.T., Chai, W., Loveless, R.W., Lawson, A.M., Margolis, R.U., Feizi, T. (1997). Brain contains HNK-1 immunoreactive O-glycans of the sulfoglucuronyl lactosamine series that terminate in 2-linked or2,6-linked hexose (mannose). J. Biol. Chem.. 272, 8924-8931.
Zhang, X., Yang, B., Shao, D., Zhao, Y., Sun, J., Li, J., Li, Y., Cao, F. (2019). Longitudinal association of subjective prospective and retrospective memory and depression among patients with glioma. Eur. J. Oncol. Nurs.. 42, 1-6.
Zhu, H., Liu, C., Rong, X., Zhang, Y., Su, M., Wang, X., Liu, M., Zhang, X., Sheng, W., Zhu, B. (2022). A new isothiocyanate-based Golgi-targeting fluorescent probe for Cys and its bioimaging applications during the Golgi stress response. Bioorg. Chem.. 122, 105741.
Zhu, X., Kaverina, I. (2013). Golgi as an MTOC: making microtubules for its own good. Histochem. Cell Biol.. 140, 361-367.

Potential therapeutic target gene/pathway	Roles related to Golgi stress response in disease	Function in disease model		Reference

		Related disease	Results by modulation of target gene/pathway
Targeting the Golgi stress response
PERK/ATF4 pathway	Inhibitor of protein translation/cell survival	HD	Upregulation of CSE and restoration of cysteine metabolism by activation of the PERK/ATF4 pathway induced by low levels of monensin treatment	( Sbodio et al., 2018)
Klotho, CREB34L/TFE3 pathway	Cell proliferation, stress response and apoptosis	Immunosenescence	Activation of CREB34L/TFE3 Golgi stress pathway and production of pro-inflammatory cytokines; Inhibition by klotho overexpression in monocyte	( Mytych et al., 2020)
GM130/CASP3	Target of TFE3 pathway; Maintenance of Golgi structure/apoptosis	HSE caused by HSV-1 infection	GM130-mediated Golgi stress and down-regulation of GM130, occludin and claudin in HSV-1 infection; Reverse effects by overexpression of GM130	( He et al., 2020)
GM130	Control of protein glycosylation and vesicle transport	ICH	Modification of Golgi morphology, GM130 decrease and autophagy by ICH; Reverse effects and neuroprotective effects by overexpression of GM130	( Deng et al., 2022)
HIF-1α/HO-1 pathway	Regulation of oxidative stress	ALI	Increase of GM130, MAN2A1, Golgin 97 and decrease of GOLPH3 by activation of HIF-1α/HO-1 pathway; Reverse effects by knockdown of HO-1	( Li et al., 2021)
CASP2	Apoptosis	HDL 17	Recovery of differentiation by knockdown of CASP2 in myelin cell accompanying AIMP2 Y35X mutation	( Ochiai et al., 2022)
Ferroptotic cell death cascade	non-apoptotic cell death characterized by iron-dependent oxidative degradation of lipids	Potential diseases related to ferroptosis; PVL, AKI, cancer, neurodegeration	Golgi stress induced by Golgi disruptors induces ferroptosis and apoptosis; Protective effect to Golgi and cell by ferroptosis inhibitor and low levels of ferroptosis inducers	( Alborzinia et al., 2018)
Targeting the Golgi-associated degradation pathways
GARD/GM130	GM130 degradation by ubiquitin-proteasome	Multiple myeloma (MM)	Activation of GM130-dependent Golgi stress response and apoptosis by monensin treatment in MM cells	( Eisenberg-Lerner et al., 2020)
EGAD	Selective protein degradation by ubiquitin-proteasome	Potential diseases by defects in proteostasis	Proteasomal degradation of Orm2 by Dsc ubiquitin ligase complex; Maintenance of sphingolipid homeostasis	( Schmidt et al., 2019)
GOMED/Wipi3	Alternative autophagy and degradation of secretory/cell membrane proteins	Diabetes	Digestion of (pro)insulin granules in Atg7 knockout β-cells	( Yamaguchi et al., 2016)
		Neurodegenerative disease	Behavioral defects, cerebellar neuronal loss and iron accumulation caused by failure of alternative autophagy in Wipi3 knockout mice	( Yamaguchi et al., 2020)