Proteasomes Can Degrade a Significant Proportion of Cellular Proteins Independent of Ubiquitination |
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Authors: | James M Baugh Evgeny V Pilipenko |
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Institution: | 1 Department of Microbiology, University of Chicago, Chicago, IL 60637, USA 2 M.P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, Moscow Region 142782, Russia |
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Abstract: | 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 (IPSs) 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 well conserved in the eukaryotic kingdom, as mammalian and yeast 20S proteasomes exhibit the same target specificity. Further, 26S proteasomes specifically recognize and cleave IPSs 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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Keywords: | UPS ubiquitin-26S proteasome system IPS intrinsic proteasome substrate IPDP intrinsic proteasome degradation pathway hnRNP heterogeneous nuclear ribonucleoprotein RRL rabbit reticulocyte lysate RSW ribosomal salt wash PRF postribosomal fraction |
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