title: Cooperative Control of Caspase Recruitment Domain-containing Protein 11 (CARD11) Signaling by an Unusual Array of Redundant Repressive Elements.
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.
authors.affiliation: From the Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Rakhi P
authors.initials: RP
authors.lastname: Jattani
authors.affiliation: From the Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Tritapoe
authors.affiliation: From the Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 joel.pomerantz@jhmi.edu.
authors.forename: Joel L
authors.identifier: http://orcid.org/0000-0002-5030-1018
authors.initials: JL
authors.lastname: Pomerantz
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
keywords: CARD11; NF-κB (NF-kB); T-cell receptor (TCR); autoinhibitory domain; diffuse large B cell lymphoma; gene regulation; lymphoma; oncogene; scaffold protein; signal transduction