MST1 Negatively Regulates TNF alpha-Induced NF-kappa B Signaling through Modulating LUBAC Activity

Abstract

The nuclear factor (NF)-kappa B pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-kappa B 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 (TNF alpha) receptor 1 signaling complex (TNF-RSC) and attenuates TNF alpha-induced NF-kappa B signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNF alpha-induced increase in I kappa B kinase (IKK) activity, as well as the expression of NF-kappa B target genes. TNF alpha 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 TNF alpha stimulation mediates the phosphorylation of HOIP and thereby inhibited LUBAC-dependent linear ubiquitination of NEMO/IKK gamma. Together, our findings suggest that MST1 negatively regulates TNF alpha-induced NF-kappa B signaling by targeting LUBAC.