Promyelocytic leukemia protein targets MK2 to promote cytotoxicity
I-Ting Chen1, Hsiao-Chi Chen1, Yu-Hsun Lo1
1Institute of Molecular Biology, Taipei, Taiwan.
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.
Insights
Promyelocytic leukemia protein (PML) promotes both apoptosis and necroptosis, crucial cell death pathways. PML deficiency enhances resistance to TNF-induced cell death by inhibiting key necroptosis signaling molecules.
Area of Science:
- Cell Biology
- Molecular Oncology
- Immunology
Background:
- Promyelocytic leukemia protein (PML) is a known tumor suppressor involved in apoptosis.
- The role of PML in other cell death pathways, such as necroptosis, remains largely unexplored.
Purpose of the Study:
- To investigate the role of PML in TNF-mediated necroptosis.
- To elucidate the molecular mechanisms by which PML regulates necroptosis and apoptosis.
Main Methods:
- Utilized Pml knockout (Pml-/-) macrophages and mice models.
- Assessed TNF-mediated necroptosis, receptor-interacting protein kinase 1 (RIPK1) activation (RIPK1[S166] phosphorylation), and necrosome complex formation (RIPK1-RIPK3-MLKL).
- Investigated the involvement of MAPK-activated kinase 2 (MK2) and p38 MAPK signaling pathways, including MK2 inhibitor treatment and MK2 knockout.
Main Results:
- Pml-/- macrophages and mice exhibited resistance to TNF-mediated necroptosis and systemic inflammatory response syndrome.
- PML deficiency led to attenuated RIPK1 activation and necrosome formation.
- PML deficiency resulted in enhanced MK2 activation and RIPK1[S321] phosphorylation, suppressing necrosome formation.
- PML directly binds and inhibits the interaction between p38 MAPK and MK2, thereby suppressing MK2 activation.
- PML deficiency attenuated autocrine TNF production.
Conclusions:
- PML promotes both apoptosis and necroptosis through distinct mechanisms.
- PML suppresses necroptosis by inhibiting p38-MK2 signaling and autocrine TNF production.
- These findings reveal a novel tumor-suppressive role for PML in regulating cell death pathways.
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