Promyelocytic leukemia protein targets MK2 to promote cytotoxicity

EMBO Rep. 2021 Dec 6;22(12):e52254. doi: 10.15252/embr.202052254. Epub 2021 Oct 11.

Abstract

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.

Keywords: MK2; PML; RIPK1; necroptosis; p38 MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Mice
  • Necroptosis
  • Phosphorylation
  • Promyelocytic Leukemia Protein / genetics
  • Promyelocytic Leukemia Protein / metabolism
  • Protein Serine-Threonine Kinases* / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases* / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Promyelocytic Leukemia Protein
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases