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      Excessive ER-phagy mediated by the autophagy receptor FAM134B results in ER stress, the unfolded protein response, and cell death in HeLa cells

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          Abstract

          Autophagy is typically a prosurvival cellular process that promotes the turnover of long-lived proteins and damaged organelles, but it can also induce cell death. We have previously reported that the small molecule Z36 induces autophagy along with autophagic cell death in HeLa cells. In this study, we analyzed differential gene expression in Z36-treated HeLa cells and found that Z36-induced endoplasmic reticulum–specific autophagy (ER-phagy) results in ER stress and the unfolded protein response (UPR). This result is in contrast to the common notion that autophagy is generally activated in response to ER stress and the UPR. We demonstrate that Z36 up-regulates the expression levels of FAM134B, LC3, and Atg9, which together mediate excessive ER-phagy, characterized by forming increased numbers of autophagosomes with larger sizes. We noted that the excessive ER-phagy accelerates ER degradation and impairs ER homeostasis and thereby triggers ER stress and the UPR as well as ER-phagy–dependent cell death. Interestingly, overexpression of FAM134B alone in HeLa cells is sufficient to impair ER homeostasis and cause ER stress and cell death. These findings suggest a mechanism involving FAM134B activity for ER-phagy to promote cell death.

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          Author and article information

          Journal
          J Biol Chem
          J. Biol. Chem
          jbc
          jbc
          JBC
          The Journal of Biological Chemistry
          American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
          0021-9258
          1083-351X
          27 December 2019
          20 November 2019
          : 294
          : 52
          : 20009-20023
          Affiliations
          []Beijing Nuclear Magnetic Resonance Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
          [§ ]BioInfoRx, Inc., Madison, Wisconsin 53719
          Author notes
          [1 ] To whom correspondence should be addressed. E-mail: binxia@ 123456pku.edu.cn .

          Edited by Xiao-Fan Wang

          Article
          PMC6937584 PMC6937584 6937584 RA119.008709
          10.1074/jbc.RA119.008709
          6937584
          31748416
          0edd1a62-b0b0-4224-9926-22e96939f9e0
          © 2019 Liao et al.

          Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

          History
          : 19 April 2019
          : 7 November 2019
          Funding
          Funded by: Ministry of Science and Technology of the People's Republic of China (MOST) , open-funder-registry 10.13039/501100002855;
          Award ID: 2016YFA0501200
          Award ID: 2012CB910703
          Award Recipient :
          Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
          Award ID: 91013011
          Award Recipient :
          Categories
          Cell Biology

          Z36,reticulophagy regulator 1 (RETREG1),FAM134B,ER-phagy,Bcl-xL inhibitor,endoplasmic reticulum (ER),unfolded protein response (UPR),endoplasmic reticulum stress (ER stress),cell death,autophagy

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