Human UFSP1 translated from an upstream near-cognate initiation codon functions as an active UFM1-specific protease.
Human UFSP1 translated from an upstream near-cognate initiation codon functions as an active UFM1-specific protease.
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从上游近同源起始密码子翻译而来的人类 UFSP1 作为活性 UFM1 特异性蛋白酶
DOI：
10.1016/j.jbc.2022.102016
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Cong, Yu-Sheng
中科院分区：
文献类型：
--
作者：
Liang, Qian;Jin, Yaqi;Xu, Shiwen;Zhou, Junzhi;Mao, Jian;Ma, Xiaohe;Wang, Miao;Cong, Yu-Sheng
泛素折叠修饰因子1(UFM1)是新近发现的一种具有重要生物学功能的泛素样译后修饰蛋白。然而，UFM1修饰靶蛋白的调控机制(UFM化)以及UFM化控制的细胞过程在很大程度上仍不清楚。已有研究表明，UFM1特异的蛋白酶(UFSP2)介导UFM1前体的成熟，并驱动去UFM化反应。此外，长期以来，人们一直认为UFSP2的同源基因UFSP1在包括人类在内的许多生物中都是不活跃的，因为当它从规范的起始密码子(445AUG)翻译过来时，缺乏一个明显的蛋白水解酶结构域。在这里，我们结合使用定点突变、CRISPR/Cas9介导的基因组编辑和质谱学方法，证明了人UFSP1的翻译始于上游近同源密码子217CUG，通过真核翻译起始因子eIF2A介导的翻译起始，而不是从注释的445AUG，揭示了包含半胱氨酸活性位点的催化蛋白酶结构域的存在。此外，我们发现UFSP1和UFSP2都介导了UFM1的成熟和靶蛋白的去UFM化。这项研究表明，人UFSP1是一种活性的UFM1特异性蛋白水解酶，从而有助于我们理解UFM化/去UFM化过程。
Ubiquitin-fold modifier 1 (UFM1) is a recently identified ubiquitin-like posttranslational modification with important biological functions. However, the regulatory mechanisms governing UFM1 modification of target proteins (UFMylation) and the cellular processes controlled by UFMylation remain largely unknown. It has been previously shown that a UFM1-specific protease (UFSP2) mediates the maturation of the UFM1 precursor and drives the de-UFMylation reaction. Furthermore, it has long been thought that UFSP1, an ortholog of UFSP2, is inactive in many organisms, including human, because it lacks an apparent protease domain when translated from the canonical start codon (445AUG). Here, we demonstrate using the combination of site-directed mutagenesis, CRISPR/Cas9–mediated genome editing, and mass spectrometry approaches that translation of human UFSP1 initiates from an upstream near-cognate codon, 217CUG, via eukaryotic translation initiation factor eIF2A-mediated translational initiation rather than from the annotated 445AUG, revealing the presence of a catalytic protease domain containing a Cys active site. Moreover, we show that both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins. This study demonstrates that human UFSP1 functions as an active UFM1-specific protease, thus contributing to our understanding of the UFMylation/de-UFMylation process.
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影响因子：
3
作者：
Kochetov AV;Palyanov A;Titov II;Grigorovich D;Sarai A;Kolchanov NA
通讯作者：
Kolchanov NA
影响因子：
6
作者：
Daniel J;Liebau E
通讯作者：
Liebau E
影响因子：
14.9
作者：
Perez-Riverol Y;Bai J;Bandla C;García-Seisdedos D;Hewapathirana S;Kamatchinathan S;Kundu DJ;Prakash A;Frericks-Zipper A;Eisenacher M;Walzer M;Wang S;Brazma A;Vizcaíno JA
通讯作者：
Vizcaíno JA
DOI：
10.1093/brain/awy135
发表时间：
2018-07-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Nahorski MS;Maddirevula S;Ishimura R;Alsahli S;Brady AF;Begemann A;Mizushima T;Guzmán-Vega FJ;Obata M;Ichimura Y;Alsaif HS;Anazi S;Ibrahim N;Abdulwahab F;Hashem M;Monies D;Abouelhoda M;Meyer BF;Alfadhel M;Eyaid W;Zweier M;Steindl K;Rauch A;Arold ST;Woods CG;Komatsu M;Alkuraya FS
通讯作者：
Alkuraya FS
影响因子：
56.9
作者：
Starck, Shelley R.;Jiang, Vivian;Shastri, Nilabh
通讯作者：
Shastri, Nilabh