Figure 8
From: The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis
HtrA2/Omi and UCH-L1 as novel components of TNF-induced necroptosis. The scheme depicts the proposed roles of HtrA2/Omi and UCH-L1 in TNF-induced necroptosis. Binding of TNF to TNF-R1 triggers activation of the necrosomal core complex consisting of RIPK1, RIPK3 and MLKL. Subsequently, the proteins PGAM5L/S and Drp-1 form the mitochondrial attack complex, resulting in the intramitochondrial activation of HtrA2/Omi. Activated HtrA2/Omi then (by cleavage of yet unidentified intramitochondrial substrates) indirectly causes monoubiquitination and activation of UCH-L1, and finally, necroptosis. Accordingly, inhibition of HtrA2/Omi (Ucf-101, knockout) or UCH-L1 (LDN57444, siRNA) protects from necroptosis. Please see Discussion for further details.