Abstract
Antigen receptor signaling to NF-κB, essential for normal lymphocyte activation, is dysregulated in several types of lymphoma. During normal signaling, the multidomain adapter CARD11 transitions from a closed, inactive state to an open, active scaffold that assembles a multiprotein complex, leading to NF-κB activation. The regulation of CARD11 scaffold function is bypassed by lymphoma-associated oncogenic CARD11 mutations that induce spontaneous signaling. We report an unbiased high-throughput quantitative signaling screen that identifies new CARD11 hyperactive variants and defines a LATCH domain that functions with the CARD to promote CARD11 autoinhibition. Gain-of-function mutations in the LATCH or CARD disrupt inhibitory domain binding, promote Bcl10 association, and induce Bcl10 ubiquitination, NF-κB activation, and human lymphoma cell survival. Our results identify CARD11 mutations with oncogenic potential, provide a mechanistic explanation for their signaling potency, and offer a straightforward method for the discovery of variants that promote the tumorigenesis of NF-κB-dependent lymphomas.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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B-Cell CLL-Lymphoma 10 Protein
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CARD Signaling Adaptor Proteins / genetics*
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CARD Signaling Adaptor Proteins / metabolism
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Caspases / genetics
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Caspases / metabolism
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Cell Survival
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Evaluation Studies as Topic
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Gene Expression Regulation
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Genetic Vectors
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Guanylate Cyclase / genetics*
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Guanylate Cyclase / metabolism
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HEK293 Cells
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High-Throughput Screening Assays
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism
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Immunoprecipitation
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Lymphocyte Activation / genetics
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Lymphoma / genetics*
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Lymphoma / metabolism
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Moloney murine leukemia virus / genetics
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Moloney murine leukemia virus / metabolism
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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Mutation
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Receptors, Antigen / genetics
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Receptors, Antigen / metabolism
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Signal Transduction*
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Ubiquitination*
Substances
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Adaptor Proteins, Signal Transducing
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B-Cell CLL-Lymphoma 10 Protein
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BCL10 protein, human
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CARD Signaling Adaptor Proteins
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NF-kappa B
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Neoplasm Proteins
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Receptors, Antigen
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I-kappa B Kinase
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Caspases
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MALT1 protein, human
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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CARD11 protein, human
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Guanylate Cyclase