PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation

Mol Cell. 2018 Jun 7;70(5):920-935.e7. doi: 10.1016/j.molcel.2018.05.016.

Seung-Won Choi ¹, Han-Hee Park ², Soyeon Kim ³, Jee Min Chung ³, Hyun-Jin Noh ², Sue Kyung Kim ⁴, Hyun Kyu Song ⁵, Chang-Woo Lee ⁶, Michael J Morgan ⁷, Ho Chul Kang ⁸, You-Sun Kim ⁹

Affiliations

1 Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea; Genomic Instability Research Center, Ajou University, School of Medicine, Suwon, Korea.
2 Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Korea.
3 Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
4 Department of Dermatology, Ajou University, School of Medicine, Suwon, Korea.
5 Department of Life Sciences, Korea University, Seoul, Korea.
6 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
7 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
8 Genomic Instability Research Center, Ajou University, School of Medicine, Suwon, Korea; Department of Physiology, Ajou University School of Medicine, Suwon, Korea. Electronic address: hckang@ajou.ac.kr.
9 Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea; Genomic Instability Research Center, Ajou University, School of Medicine, Suwon, Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Korea. Electronic address: yousunkim@ajou.ac.kr.

PMID: 29883609 DOI: 10.1016/j.molcel.2018.05.016

Abstract

Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is a central protein in Necroptosis, but posttranslational processes that regulate RIP3 activity and stability remain poorly understood. Here, we identify pellino E3 ubiquitin protein Ligase 1 (PELI1) as an E3 Ligase that targets RIP3 for proteasome-dependent degradation. Phosphorylation of RIP3 on T182 leads to interaction with the forkhead-associated (FHA) domain of PELI1 and PELI1-mediated K48-linked polyubiquitylation of RIP3 on K363. This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. PELI1-mediated RIP3 degradation effectively prevents cell death triggered by RIP3 hyperactivation. Importantly, upregulated RIP3 expression in keratinocytes from toxic epidermal necrolysis (TEN) patients is correlated with low expression of PELI1, suggesting that loss of PELI1 may play a role in the pathogenesis of TEN. We propose that PELI1 may function to control inadvertent activation of RIP3, thus preventing aberrant cell death and maintaining cellular homeostasis.

Keywords

FHA domain; PELI1; RIP3; cell death; kinase; proteasome; ubiquitylation.

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