The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the SKIV2L gene are associated with a severe inherited disorder, trichohepatoenteric syndrome (THES), with multisystem involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B cell immunodeficiency, hypogammaglobulinemia, and kappa-restricted plasma cell dyscrasia but normal T cell and NK cell function. To corroborate these findings, we made B cell–specific Skiv2l knockout mice ( Skiv2l fl/fl Cd79a-Cre ), which lacked both conventional B-2 and innate-like B-1 B cells in the periphery and secondary lymphoid organs. This was linked to a requirement of SKIV2L RNA exosome activity in the bone marrow during early B cell development at the pro–B cell to large pre–B cell transition. Mechanistically, Skiv2l -deficient pro–B cells exhibited cell cycle arrest and DNA damage. Furthermore, loss of Skiv2l led to substantial out-of-frame V(D)J rearrangement of immunoglobulin heavy chain and severely reduced surface expression of μH, both of which are crucial for pre-BCR signaling and proliferative burst during early B cell development. Together, our data demonstrated a crucial role for SKIV2L RNA exosome in early B cell development in both human and mice by ensuring proper V(D)J recombination and Igh expression, which serves as the molecular basis for immunodeficiency associated with THES.

中文翻译：

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哺乳动物 SKIV2L RNA 外泌体对于早期 B 细胞发育至关重要


SKIV2L RNA 外泌体是真核生物中进化保守的 RNA 降解复合物。突变在SKIV2L基因与严重的遗传性疾病毛肝肠综合征（THES）相关，该疾病涉及多系统，但疾病机制尚不清楚。在这里，我们报道了一名患有以下疾病的 THES 患者： SKIV2L突变显示严重的原发性 B 细胞免疫缺陷、低丙种球蛋白血症和 kappa 限制性浆细胞恶液质，但 T 细胞和 NK 细胞功能正常。为了证实这些发现，我们制作了 B 细胞特异性斯基夫2l基因敲除小鼠（斯基夫2l液量/液量CD79a-Cre ），其外周和次级淋巴器官中缺乏常规 B-2 和先天性 B-1 B 细胞。这与早期 B 细胞发育过程中前 B 细胞向大前 B 细胞转变过程中骨髓中 SKIV2L RNA 外泌体活性的需求有关。从机械上来说，斯基夫2l -缺陷的pro-B细胞表现出细胞周期停滞和DNA损伤。此外，Skiv2l 的缺失导致免疫球蛋白重链出现严重的框架外 V(D)J 重排，并严重降低 μH 的表面表达，这两者对于早期 B 细胞发育过程中的前 BCR 信号传导和增殖爆发至关重要。总之，我们的数据证明了 SKIV2L RNA 外泌体通过确保正确的 V(D)J 重组和哎呀表达，这是与 THES 相关的免疫缺陷的分子基础。