PLK1-mediated S369 phosphorylation of RIPK3 during G2 and M phases enables its ripoptosome incorporation and activity

Kartik Gupta; Bo Liu

doi:10.1016/j.isci.2021.102320

PLK1-mediated S369 phosphorylation of RIPK3 during G2 and M phases enables its ripoptosome incorporation and activity

iScience. 2021 Mar 17;24(4):102320. doi: 10.1016/j.isci.2021.102320. eCollection 2021 Apr 23.

Authors

Kartik Gupta¹, Bo Liu^{1

2}

Affiliations

¹ Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
² Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA.

Abstract

Receptor-interacting protein kinase 3 executes a form of regulated necrosis called necroptosis. Upon induction of an altered conformation by chemical inhibitors or via mutations in its kinase site, RIPK3 associates with a multiprotein complex called the ripoptosome-a signaling platform containing FADD, RIPK1, caspase 8, and cFLIP-and becomes decisive in the execution of apoptosis. Surprisingly, in contexts not completely understood, the ripoptosome itself cleaves RIPK3, highlighting an apparent conundrum on how RIPK3 fulfills its role via the complex responsible for its own degradation. Recently, ripoptosome assembly was found to occur in mitosis where we found elevated RIPK3 levels. We now report that PLK1 directly associates with RIPK3 and phosphorylates it at S369 as cells enter mitosis. G2/M phase RIPK3 has pro-apoptotic activity but upon release from ripoptosome, can trigger necroptosis. Taken together, phosphorylation of RIPK3 at S369 prevents its ripoptosome-mediated cleavage thereby retaining its pro-death activity during mitosis.

Keywords: Biological Sciences; Cell Biology; Functional Aspects of Cell Biology.

Grants and funding

R01 HL088447/HL/NHLBI NIH HHS/United States