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Mol. Cells 2013; 35(1): 41-46

Published online January 31, 2013

https://doi.org/10.1007/s10059-013-2268-y

© The Korean Society for Molecular and Cellular Biology

Ubiquilin 1 Interacts with Orai1 to Regulate Calcium Mobilization

Jeong-Eun Lee, In-Sook Jeon, Na-Eun Han, Hye-Jin Song, Eung-Gook Kim, Jae-Woon Choi, Ki-Duk Song, Hak-Kyo Lee, and Joong-Kook Choi

Division of Biochemistry, 1Division of Surgery, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea, 2Genomic Informatics Center, Hankyong National University, Ansung 456-749, Korea

Received: October 15, 2012; Accepted: October 30, 2012

Abstract

Store-operated calcium entry (SOCE) channels composed of Stim and Orai proteins play a critical role in diverse biological processes. Upon endoplasmic reticulum (ER)-mediated calcium (Ca2+) depletion, Stim proteins oligomerize with Orai to initiate Ca2+ influx across the plasma membrane. The ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains of ubiquilin 1 are involved in the degradation of presenilin and polyglutamine proteins. Through screening of Orai1 interaction partner(s) that might have an effect on SOCE, ubiquilin 1 was identified as a target of Orai1. However, the UBL and UBA domains of ubiquilin 1 were dispensable for this interaction. Additionally, ubiquilin 1 and Orai1 colocalized in the cytosolic compartment. Ubiquilin 1 increased the ubiquitination of Orai1, resulting in the formation of a high-molecular-weight form. MG132, a proteasome inhibitor, failed to block the degradation of Orai1, whereas bafilomycin A, a lysosome inhibitor, prevented Orai1 degradation. Confocal microscopy studies demonstrated that a fraction of Orai1 colocalized with ubiquilin 1 and the autophagosomal marker LC3. Because Orai1 is a constituent of SOCE, we determined the effect of
ubiquilin 1 on Orai1-mediated Ca2+ influx. As we expected, intracellular Ca2+ mobilization, a process normally potentiated by Orai1, was downregulated by ubiquilin 1. Taken together, these findings suggest that ubiquilin 1 downregulates intracellular Ca2+ mobilization and its downstream signaling by promoting the ubiquitination and lysosomal degradation of Orai1.

Keywords calcium mobilization, Orai1, Stim1, store-operated calcium entry (SOCE), ubiquilin

Article

Research Article

Mol. Cells 2013; 35(1): 41-46

Published online January 31, 2013 https://doi.org/10.1007/s10059-013-2268-y

Copyright © The Korean Society for Molecular and Cellular Biology.

Ubiquilin 1 Interacts with Orai1 to Regulate Calcium Mobilization

Jeong-Eun Lee, In-Sook Jeon, Na-Eun Han, Hye-Jin Song, Eung-Gook Kim, Jae-Woon Choi, Ki-Duk Song, Hak-Kyo Lee, and Joong-Kook Choi

Division of Biochemistry, 1Division of Surgery, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea, 2Genomic Informatics Center, Hankyong National University, Ansung 456-749, Korea

Received: October 15, 2012; Accepted: October 30, 2012

Abstract

Store-operated calcium entry (SOCE) channels composed of Stim and Orai proteins play a critical role in diverse biological processes. Upon endoplasmic reticulum (ER)-mediated calcium (Ca2+) depletion, Stim proteins oligomerize with Orai to initiate Ca2+ influx across the plasma membrane. The ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains of ubiquilin 1 are involved in the degradation of presenilin and polyglutamine proteins. Through screening of Orai1 interaction partner(s) that might have an effect on SOCE, ubiquilin 1 was identified as a target of Orai1. However, the UBL and UBA domains of ubiquilin 1 were dispensable for this interaction. Additionally, ubiquilin 1 and Orai1 colocalized in the cytosolic compartment. Ubiquilin 1 increased the ubiquitination of Orai1, resulting in the formation of a high-molecular-weight form. MG132, a proteasome inhibitor, failed to block the degradation of Orai1, whereas bafilomycin A, a lysosome inhibitor, prevented Orai1 degradation. Confocal microscopy studies demonstrated that a fraction of Orai1 colocalized with ubiquilin 1 and the autophagosomal marker LC3. Because Orai1 is a constituent of SOCE, we determined the effect of
ubiquilin 1 on Orai1-mediated Ca2+ influx. As we expected, intracellular Ca2+ mobilization, a process normally potentiated by Orai1, was downregulated by ubiquilin 1. Taken together, these findings suggest that ubiquilin 1 downregulates intracellular Ca2+ mobilization and its downstream signaling by promoting the ubiquitination and lysosomal degradation of Orai1.

Keywords: calcium mobilization, Orai1, Stim1, store-operated calcium entry (SOCE), ubiquilin

Mol. Cells
Aug 31, 2022 Vol.45 No.8, pp. 513~602
COVER PICTURE
Cryo-EM structure of human porphyrin transporter ABCB6 (main figure) shows that binding of hemin (inset, magenta) in concert with two glutathione molecules (cyan) primes ABCB6 for high ATP turnover (Kim et al., pp. 575-587).

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