MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity

Abstract

The nuclear factor (NF)-kappaB pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-kappaB signaling being implicated in various human disorders. Here, we show that mammalian ste20-like kinase 1 (MST1) is a previously unrecognized component of the tumor necrosis factor alpha (TNFalpha) receptor 1 signaling complex (TNF-RSC) and attenuates TNFalpha-induced NF-kappaB signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNFalpha-induced increase in IkappaB kinase (IKK) activity, as well as the expression of NF-kappaB target genes. TNFalpha induced the recruitment of MST1 to TNF-RSC and its interaction with HOIP, the catalytic component of the E3 ligase linear ubiquitin assembly complex (LUBAC). Furthermore, MST1 activated in response to TNFalpha stimulation mediates the phosphorylation of HOIP and thereby inhibited LUBAC-dependent linear ubiquitination of NEMO/IKKgamma. Together, our findings suggest that MST1 negatively regulates TNFalpha-induced NF-kappaB signaling by targeting LUBAC.