摘要：SummaryThe CARD11 scaffold controls antigen receptor signaling to NF-κB, JNK, and mTOR. Three classes of germline mutations in CARD11 cause Primary Immunodeficiency, including homozygous loss-of-function (LOF) mutations in CARD11 deficiency, heterozygous gain-of-function (GOF) mutations in BENTA disease, and heterozygous dominant-negative LOF mutations in CADINS. Here, we characterize LOF CARD11 mutants with a range of dominant-negative activities to identify the mechanistic properties that cause these variants to exert dominant effects when heterozygous. We find that strong dominant negatives can poison signaling from mixed wild-type:mutant oligomers at two steps in the CARD11 signaling cycle, at the Opening Step and at the Cofactor Association Step. Our findings provide evidence that CARD11 oligomer subunits cooperate in at least two steps during antigen receptor signaling and reveal how different LOF mutations in the same oligomeric signaling hub may cause disease with different inheritance patterns.Graphical abstractDisplay OmittedHighlights•Dominant-negative CARD11 mutants can disrupt the TCR-induced opening of CARD11 oligomers•Dominant-negative CARD11 mutants can also impair cofactor association with CARD11•CARD11 CARD and LATCH domain residues are required for the Opening Step•CARD domain residues coordinate at least two steps in the CARD11 signaling cycleBiochemistry; Molecular biology; Immunology
