Abstract
Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.
Highlights
Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis
As that observed in mouse embryonic fibroblast (MEF) and RGC-5 cells, in bone marrow-derived macrophages (BMDM) and mouse primary microglia stimulated by TNFα, the phosphorylation of RIPK1 S321 occurred in a similar pattern as that of IKKβ (Fig. 1d, e)
We demonstrate a novel mechanism by which phosphorylation of the intermediate domain of RIPK1 by TAK1 dictates alternative cell death mechanisms
Summary
Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. Absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1independent apoptosis and necroptosis. In cells deficient for A20, an important ubiquitin-editing enzyme for RIPK1, or TAB2, which regulates the activation of TAK1, RIPK1 may be activated to interact with RIPK3 to mediate necroptosis[7, 8] It is not clear, how activated RIPK1 might be directed to mediate two alternative modes of cell death, RDA or necroptosis, that both occur in a RIPK1 kinase-dependent manner. The molecular mechanism that controls the activation of RIPK1 kinase activity remains unclear
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