Dipeptidyl peptidase 8

Definition:

Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. Acts as a key inhibitor of caspase-1-dependent monocyte and macrophage pyroptosis in resting cells by preventing activation of NLRP1 and CARD8. Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which respectively constitute the active part of the NLRP1 and CARD8 inflammasomes, in a ternary complex, thereby preventing their oligomerization and activation. The dipeptidyl peptidase activity is required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8 are bona fide substrates of DPP8, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition (By similarity).

References:

[1]. Menghang Huang, et al. Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature. 2021 Apr;592(7856):773-777. [Content Brief]

[2]. Darren C Johnson, et al. DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes. Cell Death Dis. 2020 Aug 14;11(8):628. [Content Brief]

[3]. Darren C Johnson, et al. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med. 2018 Aug;24(8):1151-1156. [Content Brief]

[4]. L Robert Hollingsworth, et al. DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature. 2021 Apr;592(7856):778-783. [Content Brief]

[5]. Yuan-Shou Chen, et al. Purification and characterization of human prolyl dipeptidase DPP8 in Sf9 insect cells. Protein Expr Purif. 2004 May;35(1):142-6. [Content Brief]

[6]. Marian C Okondo, et al. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017 Jan;13(1):46-53. [Content Brief]

[7]. Katerina Ajami, et al. Structural requirements for catalysis, expression, and dimerization in the CD26/DPIV gene family. Biochemistry. 2003 Jan 28;42(3):694-701. [Content Brief]

[8]. Weir-Torn Jiaang, et al. Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8. Bioorg Med Chem Lett. 2005 Feb 1;15(3):687-91. [Content Brief]

[9]. C A Abbott, et al. Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur J Biochem. 2000 Oct;267(20):6140-50. [Content Brief]

[10]. Shu Y Qi, et al. Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases. Biochem J. 2003 Jul 1;373(Pt 1):179-89. [Content Brief]

[11]. Humayun Sharif, et al. Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment. Immunity. 2021 Jul 13;54(7):1392-1404.e10. [Content Brief]

[12]. Breyan Ross, et al. Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1437-E1445. [Content Brief]

[13]. Melissa R Pitman, et al. Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8). Biol Chem. 2010 Aug;391(8):959-72. [Content Brief]

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