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Daniel A Bachovchin - One of the best experts on this subject based on the ideXlab platform.

  • dpp9 directly sequesters the nlrp1 c terminus to repress inflammasome activation
    bioRxiv, 2020
    Co-Authors: Robert L Hollingsworth, Humayun Sharif, Andrew R Griswold, Pietro Fontana, Julian Mintseris, Kevin B Dagbay, Joao A Paulo, Daniel A Bachovchin, Stephen P. Gygi, Hao Wu
    Abstract:

    NLRP1 is a cytosolic inflammasome sensor that mediates activation of caspase-1, which in turn induces cytokine maturation and pyroptotic cell death. Gain-of-function NLPR1 mutations cause skin inflammatory diseases including carcinoma, keratosis, and papillomatosis. NLRP1 contains a unique function-to-find domain (FIIND) that autoproteolyzes into noncovalently associated subdomains. Proteasomal degradation of the autoinhibitory N-terminal fragment (NT) activates NLRP1 by releasing the inflammatory C-terminal fragment (CT). Cytosolic dipeptidyl peptidases 8 and 9 (DPP8/9) interact with NLRP1, and small-molecule DPP8/9 inhibitors activate NLRP1 by poorly characterized mechanisms. Here, we report cryo-EM structures of the human NLRP1-DPP9 complex, alone and in complex with the DPP8/9 inhibitor Val-boroPro (VbP). Surprisingly, the NLRP1-DPP9 complex is a ternary complex comprised of DPP9, one intact FIIND of a non-degraded full-length NLRP1 (NLRP1-FL) and one NLRP1-CT freed by NT degradation. The N-terminus of the NLRP1-CT unfolds and inserts into the DPP9 active site but is not cleaved by DPP9, and this binding is disrupted by VbP. Structure-based mutagenesis reveals that the binding of NLRP1-CT to DPP9 requires NLRP1-FL and vice versa, and inflammasome activation by ectopic NLRP1-CT expression is rescued by co-expressing autoproteolysis-deficient NLRP1-FL. Collectively, these data indicate that DPP9 functions as a "bomb-diffuser" to prevent NLRP1-CTs from inducing inflammation during homeostatic protein turnover.

  • DPP8 9 inhibitors are universal activators of functional nlrp1 alleles
    Cell Death and Disease, 2019
    Co-Authors: Marian C Okondo, Daniel A Bachovchin, Darren C Johnson, Ashley J Chui, Daniel P Ball
    Abstract:

    Intracellular pathogenic structures or activities stimulate the formation of inflammasomes, which recruit and activate caspase-1 and trigger an inflammatory form of cell death called pyroptosis. The well-characterized mammalian inflammasome sensor proteins all detect one specific type of signal, for example double-stranded DNA or bacterial flagellin. Remarkably, NLRP1 was the first protein discovered to form an inflammasome, but the pathogenic signal that NLRP1 detects has not yet been identified. NLRP1 is highly polymorphic, even among inbred rodent strains, and it has been suggested that these diverse NLRP1 alleles may have evolved to detect entirely different stimuli. Intriguingly, inhibitors of the serine proteases DPP8 and DPP9 (DPP8/9) were recently shown to activate human NLRP1, its homolog CARD8, and several mouse NLRP1 alleles. Here, we show now that DPP8/9 inhibitors activate all functional rodent NLRP1 alleles, indicating that DPP8/9 inhibition induces a signal detected by all NLRP1 proteins. Moreover, we discovered that the NLRP1 allele sensitivities to DPP8/9 inhibitor-induced and Toxoplasma gondii-induced pyroptosis are strikingly similar, suggesting that DPP8/9 inhibition phenocopies a key activity of T. gondii. Overall, this work indicates that the highly polymorphic NLRP1 inflammasome indeed senses a specific signal like the other mammalian inflammasomes.

  • inhibition of DPP8 9 activates the nlrp1b inflammasome
    Chemistry & Biology, 2018
    Co-Authors: Marian C Okondo, Darren C Johnson, Cornelius Y Taabazuing, Ashley J Chui, Sahana D Rao, Sarah E Poplawski, Daniel A Bachovchin
    Abstract:

    Summary Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases DPP8 and Dpp9 (DPP8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that DPP8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis. This work reveals a previously unrecognized mechanism for activating an innate immune pattern recognition receptor and suggests that DPP8/9 serve as an intracellular checkpoint to restrain Nlrp1b and the innate immune system.

Jingsong Zhang - One of the best experts on this subject based on the ideXlab platform.

Rahul Aggarwal - One of the best experts on this subject based on the ideXlab platform.

Xin Chen - One of the best experts on this subject based on the ideXlab platform.

  • role of a propeller loop in the quaternary structure and enzymatic activity of prolyl dipeptidases dpp iv and dpp9
    FEBS Letters, 2011
    Co-Authors: Hungkuan Tang, Kuchuan Chen, Ganguang Liou, Shuchun Cheng, Chiahui Chien, Hsiangyun Tang, Lihao Huang, Huiping Chang, Chiyuan Chou, Xin Chen
    Abstract:

    The dipeptidyl peptidase (DPP) family members, including DPP-IV, DPP8, DPP9 and others, cleave the peptide bond after the penultimate proline residue and are drug target rich. The dimerization of DPP-IV is required for its activity. A propeller loop located at the dimer interface is highly conserved within the family. Here we carried out site-directed mutagenesis on the loop of DPPIV and identified several residues important for dimer formation and enzymatic activity. Interestingly, the corresponding residues on DPP9 have a different impact whereby the mutations decrease activity without changing dimerization. Thus the propeller loop seems to play a varying role in different DPPs.

  • structure activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 DPP8 dpp9 is DPP8 selectivity an attainable goal
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Sebastiaan Van Goethem, Veerle Matheeussen, Koen Augustyns, Ingrid De Meester, Xin Chen, Annemarie Lambeir, Jurgen Joossens, Achiel Haemers, Pieter Van Der Veken
    Abstract:

    This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.

  • biochemical properties and expression profile of human prolyl dipeptidase dpp9
    Archives of Biochemistry and Biophysics, 2009
    Co-Authors: Hungkuan Tang, Chiahui Chien, Hsiangyun Tang, Shuching Hsu, Yueru Chu, Chinhang Shu, Xin Chen
    Abstract:

    Abstract Dipetidyl peptidase 9 (DPP9) is a prolyl dipeptidase preferentially cleaving the peptide bond after the penultimate proline residue. The biological function of DPP9 is unknown. In this study, we have significantly improved the yield using Strep·Tactin ® purification system and characterized the biochemical property of DPP9. Moreover, the dimer interaction mode was investigated by introducing a mutation (F842A) at the dimer interface, which abolished the enzymatic activity without disrupting its quaternary structure. Furthermore, DPP9 was found ubiquitously expressed in fibroblasts, epithelial, and blood cells. Surprisingly, contrary to previous report, we found that the expression levels of DPP8 and DPP9 did not change upon the activation of the PBMC or Jurkat cells. These results indicate that the biochemical property of DPP9 is very similar to that of DPP8, its homologous protease. DPP9 and DPP8 are likely redundant proteins carrying out overlapping functions in vivo .

  • biochemical properties of recombinant prolyl dipeptidases dpp iv and DPP8
    Advances in Experimental Medicine and Biology, 2006
    Co-Authors: Xin Chen
    Abstract:

    Dipeptidyl peptidase IV (DPP-IV, also known as CD26; EC3.4.14.5) has emerged as an important and effective drug target for the treatment of type II diabetes. It is a serine protease involved in the in vivo inactivation of two insulin-sensing hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), by cleaving the first two amino acids from their amino termini (Mentlein, 1999; Mentlein et al 1993). DPP-IV knockout mice show improved metabolic controls, including higher levels of GLP-1 and insulin, improved insulin sensitivity, reduced pancreatic islet hypertrophy, and resistance to obesity and hyperinsulinemia (Conarello et al 2003; Marguet et al 2000). Inhibition of DPP-IV activity by chemical compounds in various animal models increases the concentration of active GLP-1 and GIP in circulation, stimulates insulin secretion, and improves glucose homeostasis (Ahren et al 2002; Deacon et al 2002; Mitani et al 2002; Pospisilik et al 2002; Reimer et al 2002). Recent success in human clinical trials using DPP-IV inhibitors to treat type II diabetes validates the use of DPP-IV as a drug target for this disease, and has kindled tremendous interest in this protease from both academia and pharmaceutical companies. Its ability to cleave many hormones and chemokines in vitro and in vivo (Lambeir et al 2001; Mentlein, 1999; Proost et al 2000; Proost et al 1998; Zhu et al 2003) implicates DPPIV in various cellular functions including immunological, neuronal, and metabolic regulation, and cancer. Apart from DPP-IV, several DPP-IV-homologous proteases such as DPP8, DPP9, FAP, and DPP-II, have been identified as having prolyl-cleaving dipeptidase activity in vitro (Rosenblum and Kozarich, 2003). This group of enzymes is unique in that they cleave the peptide bond after proline or alanine at the penultimate position from the amino terminus in vitro. Because many peptide hormones or chemokines contain proline to resist degradation and cleavage by cellular proteases, the prolyl-cleaving enzymes are important in regulating the activities of these hormones and chemokines in vivo. Even though these DPP-IV-homologous proteases have been implicated in various biological functions, including cancer invasion, metastasis, cell death, and apoptosis (Rosenblum and Kozarich, 2003), their functions in vivo are not known.

Eric J Small - One of the best experts on this subject based on the ideXlab platform.