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.

WAVE 调节复合物 (WRC) 对于外周分支肌动蛋白网络的组装至关重要，该网络构成真核细胞迁移的主要驱动力之一。在这里，我们揭示了造血特异性 WRC 成分 HEM1 在免疫细胞发育中的重要作用。生殖系编码的 HEM1 缺乏是先天性免疫错误和系统性自身免疫的基础，在细胞水平上，WRC 不稳定、丝状肌动蛋白减少和无法组装板状伪足。下摆1 ^-/-小鼠表现出全身性自身免疫，表现出人类疾病的表现。在没有 Hem1 的情况下，B 细胞被剥夺了将 B 细胞受体信号传导的强度维持在允许非自身反应性 B 细胞存活的水平所必需的细胞外刺激。这将 B 细胞命运选择的平衡转向自身反应性 B 细胞，从而转向自身免疫。