Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing.
Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing.
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DOI：
10.1016/j.molcel.2021.03.004
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发表时间：
2021-05-20
期刊：
影响因子：
16
通讯作者：
Joazeiro CAP
中科院分区：
文献类型：
--
作者：
Thrun A;Garzia A;Kigoshi-Tansho Y;Patil PR;Umbaugh CS;Dallinger T;Liu J;Kreger S;Patrizi A;Cox GA;Tuschl T;Joazeiro CAP
阻碍大核糖体亚基的不完全合成的初生链被核糖体相关质量控制（RQC）靶向降解。在细菌RQC中，RqcH标记具有C-末端丙氨酸（Ala）尾的新生链，其直接被蛋白酶体样蛋白酶识别，而在真核生物中，RqcH直系同源物（Rqc 2/NEMF）协助Ltn 1/Listerin E3连接酶进行新生链泛素化。在这里，我们研究RQC介导的蛋白水解靶向核糖体失速产物在哺乳动物细胞。我们表明，哺乳动物NEMF有一个额外的，李斯特蛋白独立的蛋白水解作用，在细菌中，是由tRNA-Ala结合和Ala拖尾介导的。然而，在哺乳动物细胞中，Ala尾信号蛋白水解间接，通过识别C-末端degrons的途径，我们确定了CRL 2KLHDC 10 E3连接酶复合物和新的C-末端规则E3，Pirh 2/Rchy 1，作为真正的RQC途径的组成部分，直接结合到Ala尾核糖体失速产品和目标降解。由于李斯特蛋白突变导致小鼠神经变性，功能冗余E3可能同样涉及神经变性的分子机制。NEMF作用于核糖体相关质量控制（RQC），其靶向阻碍大核糖体亚基进行蛋白水解的初生链。NEMF同系物在细菌和酵母中的功能是通过C-末端尾部的新生链修饰介导的。这种改变是否也发生在哺乳动物中仍然未知。Thrun等人表明，人NEMF募集tRNA-Ala以修饰具有丙氨酸尾的起始链，其被E3连接酶靶向用于泛素化。
Incompletely-synthesized nascent-chains obstructing large ribosomal subunits are targeted for degradation by Ribosome-associated Quality Control (RQC). In bacterial RQC, RqcH marks the nascent-chains with C-terminal alanine (Ala) tails that are directly recognized by proteasome-like proteases, whereas in eukaryotes, RqcH orthologs (Rqc2/NEMF) assist the Ltn1/Listerin E3 ligase in nascent-chain ubiquitylation. Here we study RQC-mediated proteolytic targeting of ribosome stalling products in mammalian cells. We show that mammalian NEMF has an additional, Listerin-independent proteolytic role which, as in bacteria, is mediated by tRNA-Ala binding and Ala tailing. However, in mammalian cells Ala tails signal proteolysis indirectly, through a pathway that recognizes C-terminal degrons—we identify the CRL2KLHDC10 E3 ligase complex and the novel C-end rule E3, Pirh2/Rchy1, as bona-fide RQC pathway components that directly bind to Ala-tailed ribosome stalling products and target them for degradation. As Listerin mutation causes neurodegeneration in mice, functionally-redundant E3s may likewise be implicated in molecular mechanisms of neurodegeneration. NEMF acts in Ribosome-associated Quality Control (RQC), which targets nascent-chains obstructing large ribosomal subunits for proteolysis. The functions of NEMF homologs in bacteria and yeast are mediated by nascent-chain modification with C-terminal tails. Whether such modification also occurs in mammals has remained unknown. Thrun et al. show that human NEMF recruits tRNA-Ala to modify nascent-chains with alanine tails, which are targeted by E3 ligases for ubiquitylation.
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影响因子：
16
作者：
Lin HC;Yeh CW;Chen YF;Lee TT;Hsieh PY;Rusnac DV;Lin SY;Elledge SJ;Zheng N;Yen HS
通讯作者：
Yen HS
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：
16
作者：
Filbeck S;Cerullo F;Paternoga H;Tsaprailis G;Joazeiro CAP;Pfeffer S
通讯作者：
Pfeffer S
DOI：
10.1073/pnas.0812819106
发表时间：
2009-02-17
影响因子：
11.1
作者：
Chu, Jessie;Hong, Nancy A.;Kay, Steve A.
通讯作者：
Kay, Steve A.
影响因子：
16.6
作者：
Garzia, Aitor;Jafarnejad, Seyed Mehdi;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum