
The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity
Author(s) -
Elisabeth Salzer,
Samaneh Zoghi,
Máté G. Kiss,
Frieda Kage,
Christina Rashkova,
Stephanie Stahnke,
Matthias Haimel,
René Platzer,
Michael Caldera,
Rico Chandra Ardy,
Birgit Hoeger,
Jana Block,
Dávid Medgyesi,
Celine Sin,
Sepideh Shahkarami,
Renate Kain,
Vahid Ziaee,
Peter Hammerl,
Christoph Bock,
Jörg Menche,
Loı̈c Dupré,
Johannes B. Huppa,
Michael Sixt,
Alexis Lomakin,
Klemens Rottner,
Christoph J. Binder,
Theresia E. B. Stradal,
Nima Rezaei,
Kaan Boztuğ
Publication year - 2020
Publication title -
science immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.83
H-Index - 51
ISSN - 2470-9468
DOI - 10.1126/sciimmunol.abc3979
Subject(s) - autoimmunity , biology , microbiology and biotechnology , immune system , regulator , immunology , b cell , genetics , antibody , gene
The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1 -/- mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.