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- W4313368873 abstract "Abstract CARD11 mediates lymphocyte activation by functioning as a scaffold in antigen receptor signaling to NF-κB, JNK, and mTOR. Antigen-induced CARD11 signaling proceeds through an ordered series of steps, including Opening, Cofactor Recruitment, Enzyme Activation, and Complex Disassembly. Recently, several forms of Primary Immunodeficiency have been described that are due to germline CARD11 mutations. One of these syndromes, Combined Immunodeficiency (CID) with atopy, is inherited in an autosomal dominant manner and caused by loss-of-function (LOF) CARD11 alleles, which display dominant negative activity that poisons signaling from co-expressed wild-type CARD11. To investigate the mechanistic basis for disease-associated dominant negative activity we reconstituted CARD11-deficient T cells with a panel of LOF CARD11 variants in the absence and presence of co-expressed wild-type CARD11. In the absence of wild-type CARD11, the LOF variants were indistinguishable, such that each variant failed to promote the signal-induced 1) recruitment of the cofactors Bcl10, HOIP, and MALT1 to CARD11, 2) Bcl10 polyubiquitinylation, 3) MALT1 protease activation, 4) NF-κB activation, and 5) JNK2 activation. In the presence of co-expressed wild-type CARD11, the LOF variants surprisingly displayed a range of dominant negative activity from strong to intermediate to weak, indicating a specific potency of some mutations to disrupt signaling when heterozygous. Our results suggest that disease-associated dominant negative CARD11 mutations interfere with the Opening Step in the CARD11 signaling cycle and provide a mechanistic basis to explain why some LOF CARD11 mutations can cause disease when heterozygous while others do so when homozygous." @default.
- W4313368873 created "2023-01-06" @default.
- W4313368873 creator A5039438049 @default.
- W4313368873 creator A5088899910 @default.
- W4313368873 date "2020-05-01" @default.
- W4313368873 modified "2023-09-27" @default.
- W4313368873 title "Disease-associated dominant negative CARD11 mutations interfere with the CARD11 Opening Step during antigen receptor signaling to NF-κB and JNK2" @default.
- W4313368873 doi "https://doi.org/10.4049/jimmunol.204.supp.145.3" @default.
- W4313368873 hasPublicationYear "2020" @default.
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