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A nucleation barrier spring-loads the CBM signalosome for binary activation
Alejandro Rodriguez Gama1, Tayla Miller1, Jeffrey J Lange1
1Stowers Institute for Medical Research, Kansas City, United States.
Elife
|June 21, 2022
Summary
Immune cells activate via signalosomes, but the switch mechanism was unclear. We found BCL10 protein nucleation creates a barrier, enabling rapid immune responses and informing inflammation research.
Area of Science:
- Immunology
- Molecular Biology
- Biophysics
Background:
- Immune cell activation relies on signalosomes, large protein assemblies, yet their switch-like mechanism remains elusive.
- The CARD-BCL10-MALT1 (CBM) signalosome is crucial for nuclear transcription factor-κB (NF-κB) activation in innate and adaptive immunity.
Purpose of the Study:
- To elucidate the molecular mechanism underlying the switch-like activation of the CBM signalosome.
- To investigate the role of BCL10 polymerization in signalosome assembly and immune cell activation.
Main Methods:
- Utilized an in-cell biophysical approach to study CBM signalosome assembly.
- Employed optogenetic tools and single-cell transcriptional reporters to monitor endogenous BCL10 behavior.
- Analyzed the nucleation barrier and polymerization properties of BCL10.
Main Results:
- Identified a conserved, sequence-encoded nucleation barrier in BCL10 that controls ordered polymerization.
- Demonstrated that the specific structure of BCL10 polymers is not critical for signalosome activity.
- Revealed that endogenous BCL10 is functionally supersaturated in unstimulated human cells, predisposing them to rapid activation upon stimulation.
Conclusions:
- The switch-like activation of the CBM signalosome is governed by a nucleation-dependent polymerization process of BCL10.
- Signalosome evolution favors kinetic properties over equilibrium properties for rapid immune responses.
- Findings may offer insights into age-associated inflammation and signalosome regulation.
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