Science Bite - 3 min Oral Presentation (Students and ECRs only) Lorne Infection and Immunity 2020

Lethality due to DPP9 deficiency is rescued by deletion of the NLRP1 inflammasome (#72)

Cassandra R Harapas 1 2 , Pawat Laohamonthonkul 1 , Franklin Zhong 3 4 , Bruno Reversade 3 5 6 7 , Chien-Hsiung Yu 1 2 , Seth L Masters 1 2
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Medical Biology, The University of Melbourne, Melbourne
  3. Genome Institute of Singapore (GIS), A*STAR, Singpore
  4. Skin Research Institute of Singapore, Singapore
  5. Reproductive Biology Laboratory, Academic Medical Centre, Amsterdam-Zuidoost
  6. Department of Paediatrics, National University of Singapore, Singapore
  7. Medical Genetics Department, Koc University School of Medicine, Istanbul

The inflammasome is a protein complex nucleated by a cytoplasmic innate immune sensor, which facilitates the cleavage of pro-caspase-1 into its active form. Subsequently, caspase-1 cleaves precursor pro-inflammatory cytokines pro-IL-1b and pro-IL-18, mediating release of their active forms. Caspase-1 also cleaves GSDMD, the n-terminus of which forms pores in the plasma membrane causing pyroptosis, an inflammatory form of cell death. Several sensor components have been identified that recognise a range of microbial components and cellular stress signals. The mechanism of activation of one such pattern recognition receptor NLRP1 has yet to be fully elucidated. Previously, we identified mutations in NLRP1 that cause human autoinflammatory disease associated with overactive inflammasome formation. One of these mutations specifically triggers the NLRP1 inflammasome by preventing binding of an inhibitory protein known as DPP9.

DPP9 is a serine protease which functions to cleave Xaa-Pro dipeptides from the N- terminal of proteins. DPP9 has been implicated in NLRP1 regulation, specifically, treatment with an inhibitor of DPP9, Talabostat, activates the NLRP1 inflammasome in human and mouse cells.

Mice harboring a mutation that renders DPP9 catalytically inactivate (DPP9S279A/S279A) die within one day of birth. The cause of death is currently unknown. We have found that crossing DPP9S279A/S279A mice to NLRP1 knockout mice (NLRP1-/-) rescues lethality. DPP9S279A/S279A NLRP1-/- mice appear runted but otherwise healthy, with both males and females proving fertile. This dramatic amelioration of phenotype suggests that the major homeostatic, physiologic role of DPP9 is to prevent NLRP1 inflammasome assembly.

Our results predict that if DPP9 deficiency can be identified in humans, that it should respond to pharmacological blockade of the NLRP1 inflammasome. Although direct NLRP1 inhibitors are not yet described, downstream inhibition of inflammasome derived IL-1b and IL-18 is possible, and genetic crosses to determine the individual contribution of these cytokines to the mouse model of disease are underway.

Our studies help uncover the molecular basis for NLRP1 inflammasome activation, relevant for novel approaches to treat autoinflammatory diseases.