2. Academic Validation
  3. Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

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. doi: 10.1074/jbc.RA118.004350.
Franklin L Zhong 1 2 3 4,  Kim Robinson 2 3,  Daniel Eng Thiam Teo 5 2 3,  Kiat-Yi Tan 5,  Chrissie Lim 5,  Cassandra R Harapas 6,  Chien-Hsiung Yu 6,  William H Xie 2,  Radoslaw M Sobota 5,  Veonice Bijin Au 5,  Richard Hopkins 5,  Andrea D'Osualdo 7,  John C Reed 8,  John E Connolly 5 9 10,  Seth L Masters 6 11,  Bruno Reversade 12 2 13 14 15
Affiliations

Affiliations

  • 1 From the Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore 138673, franklin.zhong@reversade.com.
  • 2 the Institute of Medical Biology, A*STAR, Immunos, Singapore 138648.
  • 3 the Skin Research Institute of Singapore, Immunos, Singapore 138648.
  • 4 the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921.
  • 5 From the Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore 138673.
  • 6 the Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
  • 7 Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
  • 8 the Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037.
  • 9 the Institute of Biomedical Studies, Baylor University, Waco, Texas 76712.
  • 10 the Department of Microbiology and Immunology, National University of Singapore, Singapore 117545.
  • 11 the Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010 Australia.
  • 12 From the Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore 138673, bruno@reversade.com.
  • 13 the Reproductive Biology Laboratory, Obstetrics and Gynaecology, Amsterdam UMC, 1105 AZ Amsterdam-Zuidoost, The Netherlands.
  • 14 the Department of Paediatrics, National University of Singapore, Singapore 119228.
  • 15 the Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey, and.
PMID: 30291141 DOI: 10.1074/jbc.RA118.004350
Abstract

The inflammasome is a critical molecular complex that activates interleukin-1 driven inflammation in response to pathogen- and danger-associated signals. Germline mutations in the inflammasome sensor NLRP1 cause Mendelian systemic autoimmunity and skin Cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP8/9 inhibition via small molecule drugs and CRISPR/Cas9-mediated genetic deletion specifically activate the human NLRP1 inflammasome, leading to ASC speck formation, pyroptotic cell death, and secretion of cleaved interleukin-1β. Mechanistically, DPP9 interacts with a unique autoproteolytic domain (Function to Find Domain (FIIND)) found in NLRP1 and CARD8. This scaffolding function of DPP9 and its catalytic activity act synergistically to maintain NLRP1 in its inactive state and repress downstream inflammasome activation. We further identified a single patient-derived germline missense mutation in the NLRP1 FIIND domain that abrogates DPP9 binding, leading to inflammasome hyperactivation seen in the Mendelian autoinflammatory disease Autoinflammation with Arthritis and Dyskeratosis. These results unite recent findings on the regulation of murine Nlrp1b by Dpp8/9 and uncover a new regulatory mechanism for the NLRP1 inflammasome in primary human cells. Our results further suggest that DPP9 could be a multifunctional inflammasome regulator involved in human autoinflammatory diseases.

Keywords

CARD8; DPP9; NLRP1; Nod-like receptor (NLR); cell death; cellular immune response; inflammasome; inflammation.

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