Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants.
| Autor: | Bedsaul JR; Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Shah N; Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Hutcherson SM; Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Pomerantz JL; Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. |
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| Jazyk: | angličtina |
| Zdroj: | IScience [iScience] 2022 Jan 22; Vol. 25 (2), pp. 103810. Date of Electronic Publication: 2022 Jan 22 (Print Publication: 2022). |
| DOI: | 10.1016/j.isci.2022.103810 |
| Abstrakt: | 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 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. Competing Interests: The authors declare no competing interests. (© 2022 The Author(s).) |
| Databáze: | MEDLINE |
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