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Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain

The inflammasome sensor NLRP1 (nucleotide-binding oligomerization domain–like receptor containing a pyrin domain 1) detects a variety of pathogen-derived molecular patterns to induce an inflammatory immune response by triggering pyroptosis and cytokine release. A number of mutations and polymorphism...

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Autores principales: Moecking, Jonas, Laohamonthonkul, Pawat, Meşe, Kubilay, Hagelueken, Gregor, Steiner, Annemarie, Harapas, Cassandra R., Sandow, Jarrod J., Graves, Jonathan D., Masters, Seth L., Geyer, Matthias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700037/
https://www.ncbi.nlm.nih.gov/pubmed/36309085
http://dx.doi.org/10.1016/j.jbc.2022.102645
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author Moecking, Jonas
Laohamonthonkul, Pawat
Meşe, Kubilay
Hagelueken, Gregor
Steiner, Annemarie
Harapas, Cassandra R.
Sandow, Jarrod J.
Graves, Jonathan D.
Masters, Seth L.
Geyer, Matthias
author_facet Moecking, Jonas
Laohamonthonkul, Pawat
Meşe, Kubilay
Hagelueken, Gregor
Steiner, Annemarie
Harapas, Cassandra R.
Sandow, Jarrod J.
Graves, Jonathan D.
Masters, Seth L.
Geyer, Matthias
author_sort Moecking, Jonas
collection PubMed
description The inflammasome sensor NLRP1 (nucleotide-binding oligomerization domain–like receptor containing a pyrin domain 1) detects a variety of pathogen-derived molecular patterns to induce an inflammatory immune response by triggering pyroptosis and cytokine release. A number of mutations and polymorphisms of NLRP1 are known to cause autoinflammatory diseases, the functional characterization of which contributes to a better understanding of NLRP1 regulation. Here, we assessed the effect of the common NLRP1 variant M1184V, associated with asthma, inflammatory bowel disease, and diabetes, on the protein level. Our size-exclusion chromatography experiments show that M1184V stabilizes the “function-to-find” domain (FIIND) in a monomeric conformation. This effect is independent of autoproteolysis. In addition, molecular dynamics simulations reveal that the methionine residue increases flexibility within the ZU5 domain, whereas valine decreases flexibility, potentially indirectly stabilizing the catalytic triad responsible for autocleavage. By keeping the FIIND domain monomeric, formation of a multimer of full-length NLRP1 is promoted. We found that the stabilizing effect of the valine further leads to improved dipeptidyl peptidase 9 (DPP9)-binding capacities for the FIIND domain as well as the full-length protein as determined by surface plasmon resonance. Moreover, our immunoprecipitation experiments confirmed increased DPP9 binding for the M1184V protein in cells, consistent with improved formation of an autoinhibited complex with DPP9 in activity assays. Collectively, our study establishes a molecular rationale for the dichotomous involvement of the NLRP1 variant M1184V in autoimmune syndromes.
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spelling pubmed-97000372022-11-28 Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain Moecking, Jonas Laohamonthonkul, Pawat Meşe, Kubilay Hagelueken, Gregor Steiner, Annemarie Harapas, Cassandra R. Sandow, Jarrod J. Graves, Jonathan D. Masters, Seth L. Geyer, Matthias J Biol Chem Research Article The inflammasome sensor NLRP1 (nucleotide-binding oligomerization domain–like receptor containing a pyrin domain 1) detects a variety of pathogen-derived molecular patterns to induce an inflammatory immune response by triggering pyroptosis and cytokine release. A number of mutations and polymorphisms of NLRP1 are known to cause autoinflammatory diseases, the functional characterization of which contributes to a better understanding of NLRP1 regulation. Here, we assessed the effect of the common NLRP1 variant M1184V, associated with asthma, inflammatory bowel disease, and diabetes, on the protein level. Our size-exclusion chromatography experiments show that M1184V stabilizes the “function-to-find” domain (FIIND) in a monomeric conformation. This effect is independent of autoproteolysis. In addition, molecular dynamics simulations reveal that the methionine residue increases flexibility within the ZU5 domain, whereas valine decreases flexibility, potentially indirectly stabilizing the catalytic triad responsible for autocleavage. By keeping the FIIND domain monomeric, formation of a multimer of full-length NLRP1 is promoted. We found that the stabilizing effect of the valine further leads to improved dipeptidyl peptidase 9 (DPP9)-binding capacities for the FIIND domain as well as the full-length protein as determined by surface plasmon resonance. Moreover, our immunoprecipitation experiments confirmed increased DPP9 binding for the M1184V protein in cells, consistent with improved formation of an autoinhibited complex with DPP9 in activity assays. Collectively, our study establishes a molecular rationale for the dichotomous involvement of the NLRP1 variant M1184V in autoimmune syndromes. American Society for Biochemistry and Molecular Biology 2022-10-26 /pmc/articles/PMC9700037/ /pubmed/36309085 http://dx.doi.org/10.1016/j.jbc.2022.102645 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Moecking, Jonas
Laohamonthonkul, Pawat
Meşe, Kubilay
Hagelueken, Gregor
Steiner, Annemarie
Harapas, Cassandra R.
Sandow, Jarrod J.
Graves, Jonathan D.
Masters, Seth L.
Geyer, Matthias
Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain
title Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain
title_full Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain
title_fullStr Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain
title_full_unstemmed Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain
title_short Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain
title_sort inflammasome sensor nlrp1 disease variant m1184v promotes autoproteolysis and dpp9 complex formation by stabilizing the fiind domain
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700037/
https://www.ncbi.nlm.nih.gov/pubmed/36309085
http://dx.doi.org/10.1016/j.jbc.2022.102645
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