A nucleation barrier spring-loads the CBM signalosome for binary activation

Author:

Rodriguez Gama Alejandro1ORCID,Miller Tayla1,Lange Jeffrey J1,Unruh Jay R1ORCID,Halfmann Randal12ORCID

Affiliation:

1. Stowers Institute for Medical Research

2. Department of Molecular and Integrative Physiology, University of Kansas Medical Center

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 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.

Funder

National Institute of General Medical Sciences

National Institute on Aging

American Cancer Society

Stowers Institute for Medical Research

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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