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A nucleation barrier spring-loads the CBM signalosome for binary activation
Immune cells activate in binary, switch-like fashion via large protein assemblies known as signalosomes, but the molecular mechanism of the switch is not yet understood. Here, we employed an in-cell biophysical approach to dissect the assembly mechanism of the CARD-BCL10-MALT1 (CBM) signalosome, whi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9342958/ https://www.ncbi.nlm.nih.gov/pubmed/35727133 http://dx.doi.org/10.7554/eLife.79826 |
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author | Rodriguez Gama, Alejandro Miller, Tayla Lange, Jeffrey J Unruh, Jay R Halfmann, Randal |
author_facet | Rodriguez Gama, Alejandro Miller, Tayla Lange, Jeffrey J Unruh, Jay R Halfmann, Randal |
author_sort | Rodriguez Gama, Alejandro |
collection | PubMed |
description | Immune cells activate in binary, switch-like fashion via large protein assemblies known as signalosomes, but the molecular mechanism of the switch is not yet understood. Here, we employed an in-cell biophysical approach to dissect the assembly mechanism of the CARD-BCL10-MALT1 (CBM) signalosome, which governs nuclear transcription factor-κB activation in both innate and adaptive immunity. We found that the switch consists of a sequence-encoded and deeply conserved nucleation barrier to ordered polymerization by the adaptor protein BCL10. The particular structure of the BCL10 polymers did not matter for activity. Using optogenetic tools and single-cell transcriptional reporters, we discovered that endogenous BCL10 is functionally supersaturated even in unstimulated human cells, and this results in a predetermined response to stimulation upon nucleation by activated CARD multimers. Our findings may inform on the progressive nature of age-associated inflammation, and suggest that signalosome structure has evolved via selection for kinetic rather than equilibrium properties of the proteins. |
format | Online Article Text |
id | pubmed-9342958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-93429582022-08-02 A nucleation barrier spring-loads the CBM signalosome for binary activation Rodriguez Gama, Alejandro Miller, Tayla Lange, Jeffrey J Unruh, Jay R Halfmann, Randal eLife Immunology and Inflammation Immune cells activate in binary, switch-like fashion via large protein assemblies known as signalosomes, but the molecular mechanism of the switch is not yet understood. Here, we employed an in-cell biophysical approach to dissect the assembly mechanism of the CARD-BCL10-MALT1 (CBM) signalosome, which governs nuclear transcription factor-κB activation in both innate and adaptive immunity. We found that the switch consists of a sequence-encoded and deeply conserved nucleation barrier to ordered polymerization by the adaptor protein BCL10. The particular structure of the BCL10 polymers did not matter for activity. Using optogenetic tools and single-cell transcriptional reporters, we discovered that endogenous BCL10 is functionally supersaturated even in unstimulated human cells, and this results in a predetermined response to stimulation upon nucleation by activated CARD multimers. Our findings may inform on the progressive nature of age-associated inflammation, and suggest that signalosome structure has evolved via selection for kinetic rather than equilibrium properties of the proteins. eLife Sciences Publications, Ltd 2022-06-21 /pmc/articles/PMC9342958/ /pubmed/35727133 http://dx.doi.org/10.7554/eLife.79826 Text en © 2022, Rodriguez Gama et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Immunology and Inflammation Rodriguez Gama, Alejandro Miller, Tayla Lange, Jeffrey J Unruh, Jay R Halfmann, Randal A nucleation barrier spring-loads the CBM signalosome for binary activation |
title | A nucleation barrier spring-loads the CBM signalosome for binary activation |
title_full | A nucleation barrier spring-loads the CBM signalosome for binary activation |
title_fullStr | A nucleation barrier spring-loads the CBM signalosome for binary activation |
title_full_unstemmed | A nucleation barrier spring-loads the CBM signalosome for binary activation |
title_short | A nucleation barrier spring-loads the CBM signalosome for binary activation |
title_sort | nucleation barrier spring-loads the cbm signalosome for binary activation |
topic | Immunology and Inflammation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9342958/ https://www.ncbi.nlm.nih.gov/pubmed/35727133 http://dx.doi.org/10.7554/eLife.79826 |
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