Species-specific regulation of necroptosis by STK38-dependent RIPK1 phosphorylation.

Receptor-interacting protein kinase 1 (RIPK1) is a key stress sensor regulating cell death, inflammation, and tumorigenesis, yet how RIPK1 becomes activated remains unclear. Here, we identify serine/threonine kinase 38 (STK38) as a novel direct RIPK1 activator. STK38 binds to RIPK1, integrates into RIPK1-containing death complexes, and accelerates RIPK1-dependent cell death. STK38 deletion suppresses RIPK1-mediated necroptosis and apoptosis. Moreover, TNF-α stimulation triggers MEKK2-dependent STK38 activation, which in turn phosphorylates RIPK1 at serine 309, a residue conserved only in higher primates. This phosphorylation at S309 disrupts RIPK1's interaction with its inhibitory kinase MK2, thereby suppressing S320 phosphorylation and facilitating RIPK1 activation. Furthermore, colorectal cancer sample analysis revealed a positive correlation among STK38 expression, RIPK1 activation status, and favourable patient outcomes. Consistently, STK38 deficiency confers resistance to RIPK1-dependent cell death and facilitates tumour progression in a xenograft model. Our findings identify STK38 as an activator of RIPK1 and uncover a novel regulatory mechanism of RIPK1-mediated cell death in humans.