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Cited by 18NF-κB Signaling PathwaysImmune Response and InflammationGenomics and Chromatin Dynamics

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

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Rodriguez Gama, Alejandro, Miller, Tayla, Lange, Jeffrey J, Unruh, Jay R, Halfmann, Randal·2022·eLife
DOI 10.7554/elife.79826PMC PMC9342958

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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.

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Metadata

Authors
Rodriguez Gama, A., Miller, T., Lange, J. J., Unruh, J. R., & Halfmann, R.
Affiliations
  • Stowers Institute for Medical Research
  • Stowers Institute for Medical Research (US)
Corresponding author
Halfmann, Randal
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2022-06-21
Volume
11
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.79826
PMC
PMC9342958
OpenAlex
W4283263433
Cited by
18
References
3
Citations by year
2026: 4 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 1
FWCI
1.47
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of General Medical Sciences (R01GM130927)
  • National Institute on Aging (F99AG068511)
  • American Cancer Society (RSG-19-217-01-CCG)
  • Stowers Institute for Medical Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
signalosome assembly, nucleation barrier, BCL10, NF-κB activation, binary switch, immune cell activation, optogenetics, age-associated inflammation
MeSH terms
B-Cell CLL-Lymphoma 10 Protein, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Humans, Inflammation, Signal Transduction, NF-kappa B, Adaptor Proteins, Signal Transducing, CARD Signaling Adaptor Proteins

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