Cooperative control of caspase recruitment domaincontaining protein 11 (CARD11) signaling by an unusual array of redundant repressive elements

Rakhi P. Jattani, Julia M. Tritapoe, Joel L. Pomerantz

Research output: Research - peer-reviewArticle

Abstract

Several classes of signaling proteins contain autoinhibitory domains that prevent unwarranted signaling and coordinate the induction of activity in response to external cues. CARD11, a scaffold protein critical for antigen receptor signaling to NF-κB, undergoes autoregulation by a poorly understood inhibitory domain (ID), which keeps CARD11 inactive in the absence of receptor triggering through inhibitory intramolecular interactions. This autoinhibitory strategy makes CARD11 highly susceptible to gain-of-function mutations that are frequently observed in diffuse large B cell lymphoma (DLBCL) and that disrupt ID-mediated autoinhibition, leading to constitutive NF-κB activity, which can promote lymphoma proliferation. Although DLBCL-associated CARD11 mutations in the caspase recruitment domain (CARD), LATCH domain, and coiled coil have been shown to disrupt intramolecular ID binding, surprisingly, no gain-of-function mutations in the ID itself have been reported and validated. In this study, we solve this paradox and report that the CARD11 ID contains an unusual array of four repressive elements that function cooperatively with redundancy to prevent spontaneous NF-κB activation. Our quantitative analysis suggests that potent oncogenic CARD11 mutations must perturb autoinhibition by at least three repressive elements. Our results explain the lack of ID mutations in DLBCL and reveal an unusual autoinhibitory domain structure and strategy for preventing unwarranted scaffold signaling to NF-κB.

LanguageEnglish (US)
Pages8324-8336
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number16
DOIs
StatePublished - Apr 15 2016

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Caspases
Proteins
Mutation
Lymphoma, Large B-Cell, Diffuse
Scaffolds
Antigen Receptors
Cues
Lymphoma
Homeostasis
Caspase Activation and Recruitment Domain
Redundancy
Chemical activation
Cells
Chemical analysis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cooperative control of caspase recruitment domaincontaining protein 11 (CARD11) signaling by an unusual array of redundant repressive elements. / Jattani, Rakhi P.; Tritapoe, Julia M.; Pomerantz, Joel L.

In: Journal of Biological Chemistry, Vol. 291, No. 16, 15.04.2016, p. 8324-8336.

Research output: Research - peer-reviewArticle

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