Fig. 8: A model: SENP1 limits RIPK1 activation by deSUMOylation in NASH.
From: SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation
In control condition (left), SENP1 is recruited into TNF-RSC in response to TNFα in a manner dependent on RIPK1 to deSUMOylate RIPK1 in TNF-RSC and put RIPK1 in check. In SENP1 deficient condition (right), RIPK1 is hyper-SUMOylated in TNF-RSC. The SUMOylation of RIPK1 can be enhanced by PIAS1, which was also recruited by RIPK1 in TNF-RSC. Increased RIPK1 SUMOylation re-orchestrates TNF-RSC by reducing the recruitment of A20 and increasing that of LUBAC into TNF-RSC, which results in both increased K63 and M1 ubiquitination of RIPK1. Altered RIPK1 ubiquitination patterns in TNF-RSC thus promote RIPK1 activation, and license cells to die through RIPK1 kinase-dependent cell death in response to TNFα, leading to progression of NASH. Created with BioRender.com.
