1. Ligand-independent oligomerization of TACI is controlled by the transmembrane domain and regulates proliferation of activated B cells.
- Author
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Smulski CR, Zhang L, Burek M, Teixidó Rubio A, Briem JS, Sica MP, Sevdali E, Vigolo M, Willen L, Odermatt P, Istanbullu D, Herr S, Cavallari M, Hess H, Rizzi M, Eibel H, and Schneider P
- Subjects
- B-Lymphocytes, Cell Proliferation, Humans, Ligands, Common Variable Immunodeficiency genetics, Common Variable Immunodeficiency metabolism, Transmembrane Activator and CAML Interactor Protein genetics, Transmembrane Activator and CAML Interactor Protein metabolism
- Abstract
In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations., Competing Interests: Declaration of interests H.H. is employee of Merck KGaA. Other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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