Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21
Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21
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DOI：
10.1073/pnas.1507534112
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发表时间：
2015-08-11
影响因子：
11.1
通讯作者：
James, Leo C.
中科院分区：
文献类型：
--
作者：
Fletcher, Adam J.;Mallery, Donna L.;James, Leo C.
Tripartite motif (TRIM) 21是一种细胞质抗体受体，可中和穿透细胞的抗体包被病毒，同时激活先天免疫。在这里，我们发现TRIM21与k63连接的泛素（Ub-(63)Ub）结合是其双重抗病毒功能所必需的，这种结合是由非冗余E2 Ub酶的顺序活性催化的。TRIM21首先通过E2 Ube2W标记monoubiquitin （monoUb）。monoUb是异二聚体E2 Ube2N/Ube2V2的底物，产生trim21锚定的Ub-(63)Ub。E2的缺失可消除TRIM21的Ub-(63)Ub和Ub-(48)Ub结合、NF-kappa B信号和病毒中和。TRIM21-Ub-(63)Ub的形成先于蛋白酶体募集，我们发现了位于19s的降解偶联去泛素酶Poh1在TRIM21中和、信号传导和细胞因子诱导中的重要作用。本研究阐明了一步式泛素化和去泛素化活性的复杂机制，该机制允许同时存在的先天免疫信号和TRIM21的中和。
Tripartite motif (TRIM) 21 is a cytosolic antibody receptor that neutralizes antibody-coated viruses that penetrate the cell and simultaneously activates innate immunity. Here we show that the conjugation of TRIM21 with K63-linked ubiquitin (Ub-(63)Ub) catalyzed by the sequential activity of nonredundant E2 Ub enzymes is required for its dual antiviral functions. TRIM21 is first labeled with monoubiquitin (monoUb) by the E2 Ube2W. The monoUb is a substrate for the heterodimeric E2 Ube2N/Ube2V2, resulting in TRIM21-anchored Ub-(63)Ub. Depletion of either E2 abolishes Ub-(63)Ub and Ub-(48)Ub conjugation of TRIM21, NF-kappa B signaling, and virus neutralization. The formation of TRIM21-Ub-(63)Ub precedes proteasome recruitment, and we identify an essential role for the 19S-resident and degradation-coupled deubiquitinase Poh1 in TRIM21 neutralization, signaling, and cytokine induction. This study elucidates a complex mechanism of step-wise ubiquitination and deubiquitination activities that allows contemporaneous innate immune signaling and neutralization by TRIM21.