Proteasomes can degrade a significant proportion of cellular proteins independent of ubiquitination.
Proteasomes can degrade a significant proportion of cellular proteins independent of ubiquitination.
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DOI：
10.1016/j.jmb.2008.12.081
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发表时间：
2009-02-27
影响因子：
5.6
通讯作者：
Pilipenko, Evgeny V.
中科院分区：
文献类型：
--
作者：
Baugh, James M.;Viktorova, Ekaterina G.;Pilipenko, Evgeny V.
关键词：
泛素-26S蛋白酶体系统在真核生物蛋白质动态平衡调节中的重要作用已得到证实。相反，蛋白酶体不依赖泛素的蛋白分解活性的影响却知之甚少。通过对哺乳动物裂解产物的生化分析，我们发现潜伏在多肽水解过程中的20S蛋白酶体特异性地切割了所有细胞蛋白的20%以上。鉴定了30个固有蛋白酶体底物(IPs)，对它们的体外加工研究表明，它们的切割发生在无序区域，产生围绕结构域的稳定产物。IPS识别机制在真核生物中非常保守，因为哺乳动物和酵母20S蛋白酶体表现出相同的靶标特异性。此外，26S蛋白酶体在相似的位置特异性地识别和切割IPs，而不是泛素化，这表明无序区域可能构成了蛋白酶体对IPS蛋白降解的通用结构信号。最后，我们发现蛋白酶体参与了活细胞中IPS水平的生理调节，而泛素激活酶E1的失活并不能阻止IPS的降解。总而言之，这些发现表明泛素不依赖的蛋白酶体降解途径对真核生物中蛋白质稳态的调节做出了重大贡献。
The critical role of the ubiquitin-26S proteasome system in regulation of protein homeostasis in eukaryotes is well established. In contrast, the impact of the ubiquitin-independent proteolytic activity of proteasomes is poorly understood. Through biochemical analysis of mammalian lysates, we find that the 20S proteasome, latent in peptide hydrolysis, specifically cleaves more than 20% of all cellular proteins. Thirty intrinsic proteasome substrates (IPSes) were identified and in vitro studies of their processing revealed that cleavage occurs at disordered regions, generating stable products encompassing structured domains. The mechanism of IPS recognition is remarkably conserved in the eukaryotic kingdom, as mammalian and yeast 20S proteasomes exhibit the same target specificity. Further, 26S proteasomes specifically recognize and cleave IPSes at similar sites, independent of ubiquitination, suggesting that disordered regions likely constitute the universal structural signal for IPS proteolysis by proteasomes. Finally, we show that proteasomes contribute to physiological regulation of IPS levels in living cells and the inactivation of ubiquitin-activating enzyme E1 does not prevent IPS degradation. Collectively, these findings suggest a significant contribution of the ubiquitin-independent proteasome degradation pathway to the regulation of protein homeostasis in eukaryotes.
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影响因子：
8
作者：
Brignone, C;Bradley, KE;Grossman, SR
通讯作者：
Grossman, SR
DOI：
10.1159/000468685
发表时间：
1993-01-01
期刊：
ENZYME & PROTEIN
影响因子：
--
作者：
DAHLMANN, B;BECHER, B;KUEHN, L
通讯作者：
KUEHN, L
影响因子：
4.8
作者：
Kumar, S;Talis, AL;Howley, PM
通讯作者：
Howley, PM
影响因子：
16
作者：
Chen, Xueyan;Barton, Lance F.;Roberts, James M.
通讯作者：
Roberts, James M.
DOI：
10.1016/s0006-291x(03)00809-x
发表时间：
2003-06-06
影响因子：
3.1
作者：
Grune, T;Merker, K;Davies, KJA
通讯作者：
Davies, KJA