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Promyelocytic leukemia protein targets MK2 to promote cytotoxicity
Author(s) -
Chen ITing,
Chen HsiaoChi,
Lo YuHsun,
Lai PengYeh,
Hsieh FuYi,
Wu YungHsuan,
Shih HsiuMing,
Lai MingZong
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202052254
Subject(s) - necroptosis , promyelocytic leukemia protein , ripk1 , autocrine signalling , cancer research , p38 mitogen activated protein kinases , microbiology and biotechnology , kinase , programmed cell death , tumor necrosis factor alpha , chemistry , apoptosis , mapk/erk pathway , phosphorylation , caspase 8 , biology , acute promyelocytic leukemia , caspase , immunology , retinoic acid , biochemistry , receptor , gene
Promyelocytic leukemia protein (PML) is a tumor suppressor possessing multiple modes of action, including induction of apoptosis. We unexpectedly find that PML promotes necroptosis in addition to apoptosis, with Pml −/− macrophages being more resistant to TNF‐mediated necroptosis than wild‐type counterparts and PML‐deficient mice displaying resistance to TNF‐induced systemic inflammatory response syndrome. Reduced necroptosis in PML‐deficient cells is associated with attenuated receptor‐interacting protein kinase 1 (RIPK1) activation, as revealed by reduced RIPK1[S166] phosphorylation, and attenuated RIPK1‐RIPK3‐MLKL necrosome complex formation. We show that PML deficiency leads to enhanced TNF‐induced MAPK‐activated kinase 2 (MK2) activation and elevated RIPK1[S321] phosphorylation, which suppresses necrosome formation. MK2 inhibitor treatment or MK2 knockout abrogates resistance to cell death induction in PML‐null cells and mice. PML binds MK2 and p38 MAPK, thereby inhibiting p38‐MK2 interaction and MK2 activation. Moreover, PML participates in autocrine production of TNF induced by cellular inhibitors of apoptosis 1 (cIAP1)/cIAP2 degradation, since PML‐knockout attenuates autocrine TNF. Thus, by targeting MK2 activation and autocrine TNF, PML promotes necroptosis and apoptosis, representing a novel tumor‐suppressive activity for PML.