DPP8/9 inhibitors are universal activators of functional NLRP1 alleles

Cell Death & Disease
Kuo GaiDaniel A Bachovchin

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. ...Continue Reading

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Citations

Feb 14, 2020·Life Science Alliance·Daniel P BallDaniel A Bachovchin
Jun 20, 2020·Immunological Reviews·Cornelius Y TaabazuingDaniel A Bachovchin
Jun 21, 2020·Immunological Reviews·Paras K Anand
Mar 11, 2020·Cell Research·Shelbi ChristgenThirumala-Devi Kanneganti
Jul 10, 2020·International Journal of Molecular Sciences·Gabriele FeniniHans-Dietmar Beer
Aug 10, 2020·Immunological Reviews·Dhruv ChauhanMohamed Lamkanfi
Aug 17, 2020·Cell Death & Disease·Darren C JohnsonDaniel A Bachovchin
Oct 6, 2020·Current Protocols in Immunology·Haitao Guo, Jenny P-Y Ting
Nov 28, 2020·Science·Stefan BauernfriedVeit Hornung
Feb 6, 2021·Molecular Cell·Daniel A Bachovchin
May 21, 2020·Biochimica Et Biophysica Acta. General Subjects·Yakov E DunaevskyElena N Elpidina
Mar 19, 2021·Nature·Menghang HuangJijie Chai
Mar 29, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Vishal Khatri, Ramaswamy Kalyanasundaram
Jun 8, 2021·The Journal of Allergy and Clinical Immunology·Longfei WangHao Wu
Sep 19, 2019·ACS Chemical Biology·Andrew R GriswoldDaniel A Bachovchin

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Methods Mentioned

BETA
ELISA
transfection
Protein Assay
fluorescence microscopy

Software Mentioned

GraphPad Prism

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