BMB Reports 2018; 51(10): 484-485  https://doi.org/10.5483/BMBRep.2018.51.10.217
Regulation of RIP3 protein stability by PELI1-mediated proteasome-dependent degradation
Han-Hee Park1,4, Michael J. Morgan2, Ho Chul Kang3,4, and You-Sun Kim1,4,*
1Department of Biochemistry, Ajou University, School of Medicine, Oklahoma 74464, USA, 2Department of Natural Sciences, Northeastern State University, Oklahoma 74464, USA, 3Department of Physiology, Ajou University, School of Medicine, Suwon 16499, Korea, 4Department of Biomedical Sciences, Graduate School, Ajou University, Suwon 16499, Korea
Correspondence to: *Corresponding author. E-mail: yousunkim@ajou.ac.kr
Received: September 3, 2018; Published online: October 31, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is a serine-threonine kinase largely essential for necroptotic cell death; it also plays a role in some inflammatory diseases. High levels of RIP3 are likely sufficient to activate necroptotic and inflammatory pathways downstream of RIP3 in the absence of an upstream stimulus. For example, we have previously detected high levels or RIP3 in the skin of Toxic Epidermal Necrolysis patients; this correlates with increased phosphorylation of MLKL found in these patients. We have long surmised that there are molecular mechanisms to prevent anomalous activity of the RIP3 protein, and so prevent undesirable cell death and inflammatory effects when inappropriately activated. Recent discovery that Carboxyl terminus of Hsp 70-Interacting Protein (CHIP) could mediate ubiquitylation- and lysosome-dependent RIP3 degradation provides a potential protein that has this capacity. However, while screening for RIP3-binding proteins, we discovered that pellino E3 ubiquitin protein ligase 1 (PELI1) also interacts directly with RIP3 protein; further investigation in this study revealed that PELI1 also targets RIP3 for proteasome-dependent degradation. Interestingly, unlike CHIP, which targets RIP3 more generally, PELI1 preferentially targets kinase active RIP3 that has been phosphorylated on T182, subsequently leading to RIP3 degradation.

Keywords: Necroptosis, PELI1, Proteasome, RIP3, TEN
ACKNOWLEDGEMENTS

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No. 2017R1A2B3002343) and grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0554).

ABBREVIATIONS
CHIP: carboxyl terminus of Hsp 70-interacting protein
FHA: forkhead associated
PELI1: pellino E3 ubiquitin protein ligase 1
RIP3: receptor interacting protein 3
TEN: toxic epidermal necrolysis
Figures
Fig. 1. Schematic diagram of a novel, proteasome-dependent mode of RIP3 degradation mediated by an E3 ubiquitin ligase, PELI1. Phosphorylation of RIP3 on T182 leads to interaction with the FHA domain of PELI1 and PELI1-mediated K48-linked polyubiquitylation of RIP3 at K363 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.


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