Deleterious mutations in the lipopolysaccharide responsive beige-like anchor protein (LRBA) gene cause severe childhood immune dysregulation. The complexity of the symptoms involving multiple organs and the broad range of unpredictable clinical manifestations of LRBA deficiency complicate the choice of therapeutic interventions. Although LRBA has been linked to Rab11-dependent trafficking of the immune checkpoint protein CTLA-4, its precise cellular role remains elusive. We show that LRBA, however, only slightly colocalizes with Rab11. Instead, LRBA is recruited by members of the small GTPase Arf protein family to the TGN and to Rab4+ endosomes, where it controls intracellular traffic. In patient-derived fibroblasts, loss of LRBA led to defects in the endosomal pathway promoting the accumulation of enlarged endolysosomes and lysosome secretion. Thus, LRBA appears to regulate flow through the endosomal system on Rab4+ endosomes. Our data strongly suggest functions of LRBA beyond CTLA-4 trafficking and provide a conceptual framework to develop new therapies for LRBA deficiency.

中文翻译：

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Arf1 依赖性 LRBA 募集到 Rab4 内体是内溶酶体稳态所必需的。


脂多糖反应性米色样锚蛋白（LRBA）基因的有害突变会导致严重的儿童免疫失调。 LRBA 缺乏症涉及多个器官的症状的复杂性和广泛的不可预测的临床表现使治疗干预措施的选择变得复杂。尽管 LRBA 与免疫检查点蛋白 CTLA-4 的 Rab11 依赖性运输有关，但其精确的细胞作用仍然难以捉摸。然而，我们发现 LRBA 仅与 Rab11 轻微共定位。相反，LRBA 被小 GTPase Arf 蛋白家族的成员招募到 TGN 和 Rab4+ 内体，在那里它控制细胞内的运输。在患者来源的成纤维细胞中，LRBA 的缺失导致内体途径缺陷，促进内溶酶体增大和溶酶体分泌的积累。因此，LRBA 似乎可以调节 Rab4+ 内体上内体系统的流动。我们的数据强烈表明 LRBA 的功能超出了 CTLA-4 运输的范围，并为开发 LRBA 缺陷的新疗法提供了概念框架。