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Regulation of RIP3 protein stability by PELI1-mediated proteasome-dependent degradation

  • Park, Han-Hee (Department of Biochemistry, Ajou University, School of Medicine) ;
  • Morgan, Michael J. (Department of Natural Sciences, Northeastern State University) ;
  • Kang, Ho Chul (Department of Physiology, Ajou University, School of Medicine) ;
  • Kim, You-Sun (Department of Biochemistry, Ajou University, School of Medicine)
  • Received : 2018.09.03
  • Published : 2018.10.31

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

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI)