CASP10 Research Reagents

CASP10 Background

CASP10 gene encodes caspase-10, an initiator caspase that executes its role at the onset of apoptosis ^[1]. Caspase-10 carries a large N-terminal prodomain with two DEDs (death effector domains), followed by the catalytic domain containing a large and small subunit separated by a linker region ^[2][3]. Four different isoforms of caspase‐10 have been described: caspase-10a ^[2], caspase-10b ^[4], caspase-10c, and caspase-10d ^[5]. Katherine Wachmann et al. uncovered that caspase-10 shares a similar activation mechanism and intrinsic substrate preference with its closely related paralog caspase-8, though with restricted tolerance in the P4 pocket ^[12]. Upon a death stimulus, caspase-10 is expressed as a latent monomeric zymogen pro-caspase-10, which is recruited to a polymeric death-inducing signaling complex (DISC) containing the death receptors such as Fas or TRAIL, and adaptor protein FADD (Fas-associated death domain protein) ^[6][7][8][9]. These receptors are linked together through the interactions with FADD via homophilic interactions of DEDs. The DISC provides a platform for pro-caspase-10 dimerization with subsequent autocatalytic cleavage in the inter-subunit linker between their large and small chains, leading to proximity-induced activation ^[10]. Once activated, caspase-10 directly activates the executioner caspases-3 and/or caspase-7, which leads to apoptosis or inflammation by cleaving specific sets of substrates. Although highly homologous to caspase-8, caspase-10 can not substitute for caspase‐8, as the defect in apoptosis induction observed in caspase‐8‐deficient cells could not be rescued by overexpression of caspase‐10. Mutations in caspase‐10 have been shown to lead to the human ALPS II (autoimmune lymphoproliferative syndrome type II) that is characterized by a defect in T‐cell and dendritic cell apoptosis ^[11].

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[3] Fuentes-Prior P, Salvesen GS The protein structures that shape caspase activity, specificity, activation, and inhibition [J]. Biochem J. 2004 Dec 1; 384(Pt 2):201-32.
[4] Vincenz C and Dixit VM Fas‐associated death domain protein interleukin‐1β‐converting enzyme 2 (FLICE2), an ICE/Ced‐3 homologue, is proximally involved in CD95‐ and p55‐mediated death signaling [J]. J Biol Chem, 1997, 272, 6578-6583.
[5] Ng PW, Porter AG, et al. Molecular cloning and characterization of two novel pro‐apoptotic isoforms of caspase‐10 [J]. J Biol Chem, 1999, 274, 10301-10308.
[6] Scott FL, Stec B, et al. The Fas-FADD death domain complex structure unravels signaling by receptor clustering [J]. Nature. 2009;457:1019-1022.
[7] Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death [J]. Differ. 2003;10:26-35.
[8] Ashkenazi A, Dixit VM. Death receptors: signaling and modulation [J]. Science. 1998;281:1305-1308.
[9] Bodmer JL, Holler N, et al.TRAIL receptor‐2 signals apoptosis through FADD and caspase‐8 [J]. Nat Cell Biol. 2000 Apr;2(4):241-3.
[10] Boatright KM, Renatus M, et al. A unified model for apical caspase activation [J].Mol.Cell. 2003; 11:529-541.
[11] Wang J et al. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell, 1999, 98, 47-58.
[12] Katherine Wachmann, Cristina Pop, et al. Activation and Specificity of human Caspase-10 [J]. Biochemistry. 2010 Sep 28; 49(38): 8307-8315.