Szulc Natalia A, Piechota Małgorzata, Biriczová Lilla, Thapa Pankaj, Pokrzywa Wojciech
Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena Str., 02-109 Warsaw, Poland.
iScience. 2023 Oct 28;26(11):108344. doi: 10.1016/j.isci.2023.108344. eCollection 2023 Nov 17.
The ubiquitin-proteasome system (UPS) governs the degradation of proteins by ubiquitinating their lysine residues. Our study focuses on lysine deserts - regions in proteins conspicuously low in lysine residues - in averting ubiquitin-dependent proteolysis. We spotlight the prevalence of lysine deserts among bacteria leveraging the pupylation-dependent proteasomal degradation, and in the UPS of eukaryotes. To further scrutinize this phenomenon, we focused on human receptors VHL and SOCS1 to ascertain if lysine deserts could limit their ubiquitination within the cullin-RING ligase (CRL) complex. Our data indicate that the wild-type and lysine-free variants of VHL and SOCS1 maintain consistent turnover rates, unaltered by CRL-mediated ubiquitination, hinting at a protective mechanism facilitated by lysine deserts. Nonetheless, we noted their ubiquitination at non-lysine sites, alluding to alternative regulation by the UPS. Our research underscores the role of lysine deserts in limiting CRL-mediated ubiquitin tagging while promoting non-lysine ubiquitination, thereby advancing our understanding of proteostasis.
泛素-蛋白酶体系统（UPS）通过对蛋白质的赖氨酸残基进行泛素化修饰来调控蛋白质的降解。我们的研究聚焦于赖氨酸匮乏区——蛋白质中赖氨酸残基显著较少的区域——以避免泛素依赖性蛋白水解。我们利用依赖于小泛素相关修饰物（Pup）的蛋白酶体降解以及真核生物的UPS系统，突出了细菌中赖氨酸匮乏区的普遍性。为了进一步研究这一现象，我们重点研究了人类受体VHL和SOCS1，以确定赖氨酸匮乏区是否会限制它们在Cullin-RING连接酶（CRL）复合物中的泛素化修饰。我们的数据表明，VHL和SOCS1的野生型及无赖氨酸变体保持一致的周转速率，不受CRL介导的泛素化修饰影响，这暗示着赖氨酸匮乏区促成了一种保护机制。尽管如此，我们注意到它们在非赖氨酸位点发生了泛素化修饰，这表明UPS存在其他调控方式。我们的研究强调了赖氨酸匮乏区在限制CRL介导的泛素标记的同时促进非赖氨酸泛素化的作用，从而加深了我们对蛋白质稳态的理解。
