Dipeptidyl peptidase 9

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 DPP9, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition.

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]. 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]

[6]. Andrew R Griswold, et al. DPP9's Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation. ACS Chem Biol. 2019 Nov 15;14(11):2424-2429. [Content Brief]

[7]. Ruth Geiss-Friedlander, et al. The cytoplasmic peptidase DPP9 is rate-limiting for degradation of proline-containing peptides. J Biol Chem. 2009 Oct 2;284(40):27211-9. [Content Brief]

[8]. Jais R Bjelke, et al. Dipeptidyl peptidases 8 and 9: specificity and molecular characterization compared with dipeptidyl peptidase IV. Biochem J. 2006 Jun 1;396(2):391-9. [Content Brief]

[9]. 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]

[10]. 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]

[11]. 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]

[12]. Franklin L Zhong, et al. Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding. J Biol Chem. 2018 Dec 7;293(49):18864-18878. [Content Brief]

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