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Structural mechanism of CARD8 regulation by DPP9

View ORCID ProfileHumayun Sharif, View ORCID ProfileL. Robert Hollingsworth, View ORCID ProfileAndrew R. Griswold, Jeffrey C. Hsiao, Qinghui Wang, View ORCID ProfileDaniel A. Bachovchin, View ORCID ProfileHao Wu
doi: https://doi.org/10.1101/2021.01.13.426575
Humayun Sharif
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
2Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
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L. Robert Hollingsworth
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
2Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA
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Andrew R. Griswold
4Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA
5Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
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Jeffrey C. Hsiao
5Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
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Qinghui Wang
6Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Daniel A. Bachovchin
5Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
6Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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  • For correspondence: wu@crystal.harvard.edu bachovcd@mskcc.org
Hao Wu
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
2Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
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  • For correspondence: wu@crystal.harvard.edu bachovcd@mskcc.org
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SUMMARY

CARD8 is a germline-encoded pattern recognition receptor that detects intracellular danger signals. Like the related inflammasome sensor NLRP1, CARD8 undergoes constitutive autoprocessing within its function-to-find domain (FIIND), generating two polypeptides that stay associated and autoinhibited. Certain pathogen- and danger-associated activities, including the inhibition of the serine dipeptidases DPP8 and DPP9 (DPP8/9), induce the proteasome-mediated degradation of the N-terminal (NT) fragment, releasing the C-terminal (CT) fragment to form a caspase-1 activating inflammasome. DPP8/9 also bind directly to the CARD8 FIIND, but the role that this interaction plays in CARD8 inflammasome regulation is not yet understood. Here, we solved several cryo-EM structures of CARD8 bound to DPP9, with or without the DPP inhibitor Val-boroPro (VbP), which revealed a ternary complex composed of one DPP9, the full-length CARD8, and one CARD8-CT. Through structure-guided biochemical and cellular experiments, we demonstrated that DPP9’s structure restrains CARD8-CT after proteasomal degradation. Moreover, although DPP inhibitors do not directly displace CARD8 from DPP9 in vitro, we show that they can nevertheless destabilize this complex in cells. Overall, these results demonstrate that DPP8/9 inhibitors cause CARD8 inflammasome activation via at least two distinct mechanisms, one upstream and one downstream of the proteasome.

Competing Interest Statement

H.W. is a co-founder of Ventus Therapeutics. The other authors declare no competing financial interests

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 14, 2021.
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Structural mechanism of CARD8 regulation by DPP9
Humayun Sharif, L. Robert Hollingsworth, Andrew R. Griswold, Jeffrey C. Hsiao, Qinghui Wang, Daniel A. Bachovchin, Hao Wu
bioRxiv 2021.01.13.426575; doi: https://doi.org/10.1101/2021.01.13.426575
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Structural mechanism of CARD8 regulation by DPP9
Humayun Sharif, L. Robert Hollingsworth, Andrew R. Griswold, Jeffrey C. Hsiao, Qinghui Wang, Daniel A. Bachovchin, Hao Wu
bioRxiv 2021.01.13.426575; doi: https://doi.org/10.1101/2021.01.13.426575

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