title: RNF13, a RING finger protein, mediates endoplasmic reticulum stress-induced apoptosis through the inositol-requiring enzyme (IRE1α)/c-Jun NH2-terminal kinase pathway.
abstract: Disturbance of homeostasis at endoplasmic reticulum (ER) causes stress to cells that in turn triggers an adaptive signaling pathway termed unfolded protein response for the purpose of restoring normal cellular physiology or initiating signaling events leading to apoptosis. Identification of those genes that are involved in the unfolded protein response-mediated apoptotic signaling pathway would be valuable toward elucidating the molecular mechanism underlying the relationship between ER stress and apoptosis. We initiated a genetic screen by using the retroviral insertion mutation system to search for genes whose inactivation confers resistance to apoptosis induction by staurosporine. Using this approach, RING finger protein 13 (RNF13) was identified. Interestingly, RNF13 is highly enriched in ER. RNF13 knockdown cells are resistant to apoptosis and JNK activation triggered by ER stress. Conversely, overexpression of RNF13 induces JNK activation and caspase-dependent apoptosis. The RING and transmembrane domains of RNF13 are both required for its effects on JNK activation and apoptosis. Moreover, systematic analysis of the involvement of individual signaling components in the ER stress pathway using knockdown approach reveals that RNF13 acts upstream of the IRE1α-TRAF2 signaling axis for JNK activation and apoptosis. Finally, RNF13 co-immunoprecipitates with IRE1α, and the intact RING domain is also required for mediating its interaction. Together, our data support a model that RNF13 is a critical mediator for facilitating ER stress-induced apoptosis through the activation of the IRE1α-TRAF2-JNK signaling pathway.
authors: Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China; Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad 44000, Pakistan.
authors: Muhammad
authors: M
authors: Arshad
authors: Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Zhongde
authors: Z
authors: Ye
authors: Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Xiaofeng
authors: X
authors: Gu
authors: Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong 100044, China.
authors: Chung Kai
authors: CK
authors: Wong
authors: Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Yang
authors: Y
authors: Liu
authors: Center of Biomedical Analysis, Tsinghua University, Beijing 100084, China.
authors: De
authors: Li
authors: Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Linkang
authors: L
authors: Zhou
authors: Institute of Molecular and Cell Biology, A-STAR, Republic of Singapore 138673.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Pharmacy, National University of Singapore, Republic of Singapore 119077.
authors: Wan Ping
authors: WP
authors: Bay
authors: Department of Pharmacy, National University of Singapore, Republic of Singapore 119077.
authors: Victor C
authors: VC
authors: Yu
authors: Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: li-peng@mail.tsinghua.edu.cn.
authors: Peng
authors: P
authors: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D054829:RING Finger Domains; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C540080:RNF13 protein, human; D044767:Ubiquitin-Protein Ligases; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases
references: Physiol Genomics. 2005 Jun 16;22(1):8-13
references: 15797969
references: Science. 2000 May 5;288(5467):870-4
references: 10797012
references: Mol Cell. 2000 Dec;6(6):1355-64
references: 11163209
references: PLoS One. 2010 Mar 08;5(3):e9575
references: 20221394
references: Science. 2011 Nov 25;334(6059):1081-6
references: 22116877
references: J Biol Chem. 2009 Jan 16;284(3):1593-603
references: 19004820
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364
references: PLoS One. 2011;6(9):e24660
references: 21949742
references: FEBS J. 2010 Jan;277(2):466-76
references: 20015074
references: Int J Cell Biol. 2010;2010:830307
references: 20169136
references: Cell. 2007 Jun 29;129(7):1337-49
references: 17604722
references: Oncogene. 1999 Oct 14;18(42):5814-20
references: 10523862
references: Methods. 2005 Apr;35(4):395-416
references: 15804613
references: Semin Cell Dev Biol. 2007 Dec;18(6):716-31
references: 18023214
references: J Cell Sci. 2004 Sep 15;117(Pt 20):4673-80
references: 15371523
references: Science. 2000 Jan 28;287(5453):664-6
references: 10650002
references: Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3105-9
references: 8610176
references: Nat Cell Biol. 2011 Mar;13(3):184-90
references: 21364565
references: Nature. 2003 Dec 18;426(6968):891-4
references: 14685249
references: Trends Mol Med. 2012 Jan;18(1):59-68
references: 21889406
references: Physiol Rev. 2011 Oct;91(4):1219-43
references: 22013210
references: Cell. 2008 Jan 11;132(1):89-100
references: 18191223
references: Anal Biochem. 1999 Dec 1;276(1):88-96
references: 10585748
references: Nat Rev Drug Discov. 2008 Dec;7(12):1013-30
references: 19043451
references: Cardiovasc Res. 2007 Jan 1;73(1):48-56
references: 17107669
references: Nat Cell Biol. 2003 Dec;5(12):1083-9
references: 14634665
references: Cell Res. 2009 Mar;19(3):348-57
references: 18794910
references: J Biol Chem. 2004 Nov 26;279(48):50375-81
references: 15452118
references: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2432-7
references: 12591950