A nucleation barrier spring-loads the CBM signalosome for binary activation
- Stowers Institute for Medical Research, United States
Abstract
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 NF-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.
Data availability
Original data underlying this manuscript can be accessed from the Stowers Original Data Repository at http://www.stowers.org/research/publications/libpb-1675
Article and author information
Author details
Alejandro Rodriguez Gama
Funding
National Institutes of Health (R01GM130927)
- Randal Halfmann
National Institutes of Health (F99AG068511)
- Alejandro Rodriguez Gama
American Cancer Society (RSG-19-217-01-CCG)
- Randal Halfmann
Stowers Institute for Medical Research
- Jay R Unruh
- Randal Halfmann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Rodriguez Gama et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A nucleation barrier spring-loads the CBM signalosome for binary activation
eLife 11:e79826.
https://doi.org/10.7554/eLife.79826
