TSG101 Physically Interacts with Linear Ubiquitin Chain Assembly Complex (LUBAC) and Upregulates the TNF-Induced NF-KB Activation

Linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin E3 ligase complex composed of HOIP, HOIL-1L, and SHARPIN that catalyzes the formation of linear/M1linked ubiquitin chain. It has been shown to play a pivotal role in the nuclear factor (NF)-KB signaling induced by proinflammatory stimuli. Here, we found that tumor susceptibility gene (TSG101) physically interacts with HOIP, a catalytic component of LUBAC, and potentiates LUBAC activity. Depletion of TSG101 expression by RNA interference decreased TNFa-induced linear ubiquitination and the formation of TNFa receptor 1 signaling complex (TNFRSC). Furthermore, TSG101 facilitated the TNFa-induced stimulation of the NF-KB pathway. Thus, we suggest that TSG101 functions as a positive modulator of HOIP that mediates TNFa-induced NF-KB signaling pathway.