2. Academic Validation
  3. Transmembrane E3 ligase RNF183 mediates ER stress-induced apoptosis by degrading Bcl-xL

Transmembrane E3 ligase RNF183 mediates ER stress-induced apoptosis by degrading Bcl-xL

  • Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2762-E2771. doi: 10.1073/pnas.1716439115.
Yanfang Wu 1 2,  Xia Li 1 2,  Junying Jia 3,  Yanpeng Zhang 4,  Jing Li 5,  Zhengmao Zhu 5,  Huaqing Wang 6,  Jie Tang 1,  Junjie Hu 7 2
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, Chinese Academy of Sciences (CAS) Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, 100101 Beijing, China.
  • 2 College of Life Sciences, University of CAS, 100101 Beijing, China.
  • 3 Protein Science Core Facility Center, Institute of Biophysics, CAS, 100101 Beijing, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.
  • 5 Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 300071 Tianjin, China.
  • 6 Department of Oncology, Institute of Integrative Oncology, Tianjin Union Medical Center, 300121 Tianjin, China.
  • 7 National Laboratory of Biomacromolecules, Chinese Academy of Sciences (CAS) Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, 100101 Beijing, China; [email protected].
PMID: 29507230 DOI: 10.1073/pnas.1716439115
Abstract

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and triggers the unfolded protein response (UPR). Failure to resolve ER stress leads to apoptotic cell death via a yet unclear mechanism. Here, we show that RNF183, a membrane-spanning RING finger protein, localizes to the ER and exhibits classic E3 ligase activities. Sustained ER stress induced by different treatments increases RNF183 protein levels posttranscriptionally in an IRE1α-dependent manner. Activated IRE1 reduces the level of miR-7, which increases the stability of RNF183 transcripts. In addition, overexpression of RNF183 leads to increased Apoptosis and its depletion alleviates ER stress-induced Apoptosis. Furthermore, RNF183 interacts with Bcl-xL, an antiapoptotic member of the Bcl-2 Family, and polyubiquitinates Bcl-xL for degradation. Thus, RNF183 plays an important role in executing programmed cell death upon prolonged ER stress, likely by inducing Apoptosis through Bcl-xL.

Keywords

Bcl-xL; RING finger protein; apoptosis; endoplasmic reticulum stress; unfolded protein response.

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