Caspase 10

Caspase-10 (CASP10) functions as an initiator caspase in death receptor signaling and can initiate Fas- and TRAIL-receptor-mediated apoptosis independently of caspase-8^[1]. Mechanistically, caspase-10 is recruited to native TRAIL and CD95/Fas death-inducing signaling complexes (DISC) in a FADD-dependent manner, but it cannot functionally substitute caspase-8 in caspase-8-deficient cells^[2]. Compared with caspase-8, caspase-10 acts as a regulatory isoform that reduces caspase-8 DISC association and activation, thereby switching CD95L signaling toward NF-κB activation and cell survival^[3]. Caspase-8 and caspase-10 also activate NF-κB through RIP, NIK, and IKKα kinases, linking apoptotic machinery to inflammatory gene regulation^[4]. In primary biliary cholangitis models, caspase-10 knockout macrophages showed stronger regulation of inflammatory cell death than caspase-8 knockout macrophages, including necroptosis and pyroptosis^[5]. CASP10 mutations were reported in autoimmune lymphoproliferative syndrome type II with defective lymphocyte and dendritic cell apoptosis, but later human variant analyses found CASP10 dispensable for Fas-mediated apoptosis and unlikely to drive ALPS pathogenesis^[6][7]. Substrate studies show overlapping caspase-8/caspase-10 cleavage preferences for RIP and PAK2, but distinct Bid cleavage patterns^[8]. For experimental applications, the caspase-10 inhibitor z-AEVD-Fmk reduced terminal erythroid differentiation in CD36⁺ cultures, supporting pathway-specific functional testing^[9].