The mammalian SKIV2L RNA exosome is essential for early B cell development.
The mammalian SKIV2L RNA exosome is essential for early B cell development.
复制标题
DOI：
10.1126/sciimmunol.abn2888
复制
发表时间：
2022-06-03
影响因子：
24.8
通讯作者：
Yan, Nan
中科院分区：
文献类型：
--
作者：
Yang, Kun;Han, Jie;Gill, Jennifer G.;Park, Jason Y.;Sathe, Meghana N.;Gattineni, Jyothsna;Wright, Tracey;Wysocki, Christian;de la Morena, M. Teresa;Yan, Nan
SKIV 2L RNA外泌体是真核生物中进化上保守的RNA降解复合物。SKIV 2L基因突变与严重的遗传性疾病，肝肠综合征（THES），多系统参与，但未知的疾病机制。在这里，我们报告了一个SKIV 2L突变的THES患者，表现出严重的原发性B细胞免疫缺陷，低丙种球蛋白血症，κ-限制性浆细胞恶液质，但正常的T细胞和NK细胞功能。为了证实这些发现，我们制备了B细胞特异性Skiv 2l敲除小鼠（Skiv 2lfl/flCd 79 a-Cre），其在外周和次级淋巴器官中缺乏常规B-2和先天样B-1 B细胞。这与在前B向大的前B转变的早期B细胞发育期间骨髓中SKIV 2L RNA外泌体活性的需要有关。从机制上讲，Skiv 2l缺陷的pro-B细胞表现出细胞周期停滞和DNA损伤。此外，Skiv 2l的缺失导致免疫球蛋白重链的实质性框外V（D）J重排和μH的表面表达的严重降低，这两者对于早期B细胞发育期间的前BCR信号传导和增殖爆发都是至关重要的。总之，我们的数据证明了SKIV 2L RNA外泌体在人和小鼠的早期B细胞发育中的关键作用，其通过确保适当的V（D）J重组和Igh表达，其作为与THES相关的免疫缺陷的分子基础。SKIV 2L RNA外泌体对于V（D）J重组和早期B细胞发育期间的前B到大前B的转变是必需的。
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 multi-system involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B-cell immunodeficiency, hypogammaglobulinemia, 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 (Skiv2lfl/flCd79a-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 to large pre-B 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 cells 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 serve as the molecular basis for immunodeficiency associated with THES. SKIV2L RNA exosome is essential for V(D)J recombination and the pro-B to large pre-B transition during early B cell development.
登录
查看更多内容
影响因子：
64.8
作者：
Ba Z;Lou J;Ye AY;Dai HQ;Dring EW;Lin SG;Jain S;Kyritsis N;Kieffer-Kwon KR;Casellas R;Alt FW
通讯作者：
Alt FW
DOI：
10.1261/rna.064626.117
发表时间：
2018-03
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Morton DJ;Kuiper EG;Jones SK;Leung SW;Corbett AH;Fasken MB
通讯作者：
Fasken MB
影响因子：
64.5
作者：
Halbach, Felix;Reichelt, Peter;Conti, Elena
通讯作者：
Conti, Elena
影响因子：
64.8
作者：
Pefanis, Evangelos;Wang, Jiguang;Rothschild, Gerson;Lim, Junghyun;Chao, Jaime;Rabadan, Raul;Economides, Aris N.;Basu, Uttiya
通讯作者：
Basu, Uttiya
影响因子：
7.3
作者：
Vély F;Barlogis V;Marinier E;Coste ME;Dubern B;Dugelay E;Lemale J;Martinez-Vinson C;Peretti N;Perry A;Bourgeois P;Badens C;Goulet O;Hugot JP;Farnarier C;Fabre A
通讯作者：
Fabre A