Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants.

ABSTRACT: The 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 oli

SUBMITTER: Bedsaul JR 

PROVIDER: S-EPMC8844825 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature