The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells.
The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells.
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DOI：
10.15252/embj.201490332
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发表时间：
2014-12-17
期刊：
影响因子：
--
通讯作者：
Martinez J
中科院分区：
文献类型：
--
作者：
Jurkin J;Henkel T;Nielsen AF;Minnich M;Popow J;Kaufmann T;Heindl K;Hoffmann T;Busslinger M;Martinez J
未折叠蛋白反应（unfolded protein response，UPR）是内质网（endoplasmic reticulum，ER）内未折叠蛋白积累后激活的一条保守的应激信号通路。活跃的UPR信号传导导致XBP1 mRNA的非常规酶促剪接，使得转录因子XBP1的表达能够控制ER稳态。虽然IRE1已被鉴定为切割该mRNA所需的核糖核酸内切酶，但哺乳动物细胞中的相应连接酶仍然难以捉摸。在这里，我们报告RTCB，tRNA连接酶复合物的催化亚基，及其辅助因子archease介导的体外和体内的XBP1 mRNA剪接。RTCB在Rtcbfl/fl Cd23-Cre小鼠的浆细胞中的耗尽阻止了XBP1s表达，其通常在浆细胞发育期间被强烈诱导。RTCB耗尽的浆细胞显示减少和紊乱的ER结构以及抗体分泌的严重缺陷。因此，靶向RTCB和/或archease代表了用于治疗越来越多的与XBP1表达升高相关的疾病的有希望的策略。
The unfolded protein response (UPR) is a conserved stress-signaling pathway activated after accumulation of unfolded proteins within the endoplasmic reticulum (ER). Active UPR signaling leads to unconventional, enzymatic splicing of XBP1 mRNA enabling expression of the transcription factor XBP1s to control ER homeostasis. While IRE1 has been identified as the endoribonuclease required for cleavage of this mRNA, the corresponding ligase in mammalian cells has remained elusive. Here, we report that RTCB, the catalytic subunit of the tRNA ligase complex, and its co-factor archease mediate XBP1 mRNA splicing both in vitro and in vivo. Depletion of RTCB in plasma cells of Rtcbfl/fl Cd23-Cre mice prevents XBP1s expression, which normally is strongly induced during plasma cell development. RTCB-depleted plasma cells show reduced and disorganized ER structures as well as severe defects in antibody secretion. Targeting RTCB and/or archease thus represents a promising strategy for the treatment of a growing number of diseases associated with elevated expression of XBP1s.
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影响因子：
64.5
作者：
Karaca E;Weitzer S;Pehlivan D;Shiraishi H;Gogakos T;Hanada T;Jhangiani SN;Wiszniewski W;Withers M;Campbell IM;Erdin S;Isikay S;Franco LM;Gonzaga-Jauregui C;Gambin T;Gelowani V;Hunter JV;Yesil G;Koparir E;Yilmaz S;Brown M;Briskin D;Hafner M;Morozov P;Farazi TA;Bernreuther C;Glatzel M;Trattnig S;Friske J;Kronnerwetter C;Bainbridge MN;Gezdirici A;Seven M;Muzny DM;Boerwinkle E;Ozen M;Baylor Hopkins Center for Mendelian Genomics;Clausen T;Tuschl T;Yuksel A;Hess A;Gibbs RA;Martinez J;Penninger JM;Lupski JR
通讯作者：
Lupski JR
影响因子：
64.8
作者：
Chen, Xi;Iliopoulos, Dimitrios;Zhang, Qing;Tang, Qianzi;Greenblatt, Matthew B.;Hatziapostolou, Maria;Lim, Elgene;Tam, Wai Leong;Ni, Min;Chen, Yiwen;Mai, Junhua;Shen, Haifa;Hu, Dorothy Z.;Adoro, Stanley;Hu, Bella;Song, Minkyung;Tan, Chen;Landis, Melissa D.;Ferrari, Mauro;Shin, Sandra J.;Brown, Myles;Chang, Jenny C.;Liu, X. Shirley;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
影响因子：
32.4
作者：
Kwon, Kyongrim;Hutter, Caroline;Busslinger, Meinrad
通讯作者：
Busslinger, Meinrad
影响因子：
14.9
作者：
FILIPOWICZ, W;KONARSKA, M;SHATKIN, AJ
通讯作者：
SHATKIN, AJ
影响因子：
30.5
作者：
Hasbold, J;Corcoran, LM;Hodgkin, PD
通讯作者：
Hodgkin, PD