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Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation

ABSTRACT: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Early Embryonic Cell

DISEASE(S): Disease Free

SUBMITTER: Hailin Tu

LAB HEAD: Xin Lin

PROVIDER: PXD036995 | Pride | 2022-10-12

REPOSITORIES: Pride

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			Action	DRS
	MS200773-1.msf	Msf
	MS200773-1.raw	Raw
	MS200773-2.msf	Msf
	MS200773-2.raw	Raw
	checksum.txt	Txt

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