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

Seung Won Choi, Han Hee Park, Soyeon Kim, Jee Min Chung, Hyun Jin Noh, Sue Kyung Kim, Hyun Kyu Song, Chang Woo Lee, Michael J. Morgan, Ho Chul Kang, You Sun Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. Choi et al. show that PELI1-mediated K48-linked polyubiquitylation of kinase-active RIP3 leads to its proteasome-dependent degradation. Regulation of activated RIP3 by PELI1 provides a homeostatic mechanism to prevent aberrant cell death and minimize necroptotic pathology that occurs in diseases such as toxic epidermal necrolysis.

Original languageEnglish
Pages (from-to)920-935.e7
JournalMolecular Cell
Volume70
Issue number5
DOIs
Publication statusPublished - 2018 Jun 7

Keywords

  • FHA domain
  • PELI1
  • RIP3
  • cell death
  • kinase
  • proteasome
  • ubiquitylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation'. Together they form a unique fingerprint.

Cite this