Promyelocytic leukemia protein targets MK2 to promote cytotoxicity

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. SYNOPSIS Promyelocytic leukemia protein promotes TNF-induced necroptosis via two distinct pathways, firstly by inhibiting MAPK activated kinase 2 activation, and secondly by enhancing autocrine TNF generation. Promyelocytic leukemia protein (PML) promotes necroptosis. PML targets MAPK activated kinase 2 (MK2) and inhibits MK2 activation to enhance necroptosis. PML also increases autocrine production of tumor necrosis factor (TNF) and associated necroptosis induction. Graphical Abstract Promyelocytic leukemia protein promotes TNF-induced necroptosis via two distinct pathways, firstly by inhibiting MAPK activated kinase 2 activation, and secondly by enhancing autocrine TNF generation.