Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T-cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28BR25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b 211 C > T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.
A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly / Capitani N.; Onnis A.; Finetti F.; Cassioli C.; Plebani A.; Brunetti J.; Troilo A.; D'Elios S.; Baronio M.; Gazzurelli L.; Della Bella C.; Billadeau D.D.; D'Elios M.M.; Lougaris V.; Baldari C.T.. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - STAMPA. - (2021), pp. 1-17. [10.1038/s41418-021-00837-5]
A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly
Capitani N.;Plebani A.;Troilo A.;Baronio M.;Della Bella C.;D'Elios M. M.;
2021
Abstract
Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T-cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28BR25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b 211 C > T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.File | Dimensione | Formato | |
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