The Cytoskeletal Regulator Hem1 Governs B Cell Development and Prevents Autoimmunity Publisher Pubmed



Salzer E^{1, 2, 3, 4} ; Zoghi S^{1, 2, 3, 5, 6} ; Kiss MG^{3, 7} ; Kage F^{8, 9} ; Rashkova C^{1, 3, 10} ; Stahnke S⁹ ; Haimel M^{1, 2, 3} ; Platzer R¹¹ ; Caldera M³ ; Ardy RC^{1, 2, 3} ; Hoeger B^{1, 2, 3} ; Block J^{1, 2, 3} ; Medgyesi D¹ ; Sin C³ Show All Authors
Source: Science Immunology Published:2020

Abstract

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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works