Molecules and Cells

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Fig. 1. The inhibition of the UPS results in the compensatory activation of autophagy. Proteasomal inhibition in the ER impairs ERAD and causes ER stress and the UPR. PERK and IRE1α subsequently activate downstream pathways toward autophagy. The PERK- eIF2α circuit accelerates the synthesis of the transcription factors ATF4 and CHOP, leading to the expression of ATG genes. Activated IRE1 recruits TRAF2, leading to the phosphorylation of JNK and the expression of autophagic core genes. In parallel, ATF6 is cleaved in the Golgi and translocates to the nucleus, where it induces the expression of DAPK1 and its phosphorylation of beclin-1 for autophagosome biogenesis. In addition, accumulated p53 upon proteasomal inhibition translocates to the nucleus and acts as a transcription factor for autophagy housekeeping genes such as DRAM. Alternatively, increased p53 levels may activate AMPK-dependent autophagy by inhibiting the mTOR pathway.
Mol. Cells 2017;40:441~449
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