Abstract
The cellular proteome is a complex microcosm of structural and regulatory networks that requires continuous surveillance and modification to meet the dynamic needs of the cell. It is therefore crucial that the protein flux of the cell remains in balance to ensure proper cell function. Genetic alterations that range from chromosome imbalance to oncogene activation can affect the speed, fidelity and capacity of protein biogenesis and degradation systems, which often results in proteome imbalance. An improved understanding of the causes and consequences of proteome imbalance is helping to reveal how these systems can be targeted to treat diseases such as cancer.
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References
Nagaraj, N. et al. Deep proteome and transcriptome mapping of a human cancer cell line. Mol. Syst. Biol. 7, 548 (2011).
Schwanhäusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
Wiśniewski, J. R., Hein, M. Y., Cox, J. & Mann, M. A “proteomic ruler” for protein copy number and concentration estimation without spike-in standards. Mol. Cell. Proteomics 13, 3497–3506 (2014).
Jünger, M. A. & Aebersold, R. Mass spectrometry-driven phosphoproteomics: patterning the systems biology mosaic. Wiley Interdiscip. Rev. Dev. Biol. 3, 83–112 (2014).
Hornbeck, P. V. et al. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 43, D512–D520 (2015).
Pan, Q., Shai, O., Lee, L. J., Frey, B. J. & Blencowe, B. J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genet. 40, 1413–1415 (2008).
Buszczak, M., Signer, R. A. & Morrison, S. J. Cellular differences in protein synthesis regulate tissue homeostasis. Cell 159, 242–251 (2014).
Jovanovic, M. et al. Dynamic profiling of the protein life cycle in response to pathogens. Science 347, 1259038 (2015).
Liu, Y., Beyer, A. & Aebersold, R. On the dependency of cellular protein levels on mRNA abundance. Cell 165, 535–550 (2016).
The 1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).
Garraway, L. A. & Lander, E. S. Lessons from the cancer genome. Cell 153, 17–37 (2013).
Zhang, B. et al. Proteogenomic characterization of human colon and rectal cancer. Nature 513, 382–387 (2014).
Ingolia, N. T. Ribosome profiling: new views of translation, from single codons to genome scale. Nature Rev. Genet. 15, 205–213 (2014).
Kim, M. S. et al. A draft map of the human proteome. Nature 509, 575–581 (2014).
Vogel, C. & Marcotte, E. M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nature Rev. Genet. 13, 227–232 (2012).
Wang, M., Herrmann, C. J., Simonovic, M., Szklarczyk, D. & von Mering, C. Version 4.0 of PaxDb: protein abundance data, integrated across model organisms, tissues, and cell-lines. Proteomics 15, 3163–3168 (2015).
Wilhelm, M. et al. Mass-spectrometry-based draft of the human proteome. Nature 509, 582–587 (2014).
Dever, T. E. & Green, R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb. Perspect. Biol. 4, a013706 (2012).
Rodrigo-Brenni, M. C. & Hegde, R. S. Design principles of protein biosynthesis-coupled quality control. Dev. Cell 23, 896–907 (2012).
Sonenberg, N. & Hinnebusch, A. G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009).
Bhat, M. et al. Targeting the translation machinery in cancer. Nature Rev. Drug Discov. 14, 261–278 (2015).
Deshaies, R. J. Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy. BMC Biol. 12, 94 (2014).
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Hsieh, A. L., Walton, Z. E., Altman, B. J., Stine, Z. E. & Dang, C. V. MYC and metabolism on the path to cancer. Semin. Cell Dev. Biol. 43, 11–21 (2015).
Ruggero, D. Translational control in cancer etiology. Cold Spring Harb. Perspect. Biol. 5, (2013).
Wong, K. K., Engelman, J. A. & Cantley, L. C. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20, 87–90 (2010).
Basan, M. et al. Inflating bacterial cells by increased protein synthesis. Mol. Syst. Biol. 11, 836 (2015).
Scott, M., Klumpp, S., Mateescu, E. M. & Hwa, T. Emergence of robust growth laws from optimal regulation of ribosome synthesis. Mol. Syst. Biol. 10, 747 (2014).
Drummond, D. A. & Wilke, C. O. The evolutionary consequences of erroneous protein synthesis. Nature Rev. Genet. 10, 715–724 (2009).
Zaher, H. S. & Green, R. Fidelity at the molecular level: lessons from protein synthesis. Cell 136, 746–762 (2009).
Doherty, M. K., Hammond, D. E., Clague, M. J., Gaskell, S. J. & Beynon, R. J. Turnover of the human proteome: determination of protein intracellular stability by dynamic SILAC. J. Proteome Res. 8, 104–112 (2009).
Boisvert, F.-M. et al. A quantitative spatial proteomics analysis of proteome turnover in human cells. Mol. Cell. Proteomics 11, M111.011429 (2012).
Duttler, S., Pechmann, S. & Frydman, J. Principles of cotranslational ubiquitination and quality control at the ribosome. Mol. Cell 50, 379–393 (2013).
Wang, F., Durfee, L. A. & Huibregtse, J. M. A cotranslational ubiquitination pathway for quality control of misfolded proteins. Mol. Cell 50, 368–378 (2013).
Ingolia, N. T., Lareau, L. F. & Weissman, J. S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147, 789–802 (2011).
Peth, A., Nathan, J. A. & Goldberg, A. L. The ATP costs and time required to degrade ubiquitinated proteins by the 26 S proteasome. J. Biol. Chem. 288, 29215–29222 (2013).
Asano, S. et al. A molecular census of 26S proteasomes in intact neurons. Science 347, 439–442 (2015).
Gendron, J. M. et al. Using the ubiquitin-modified proteome to monitor distinct and spatially restricted protein homeostasis dysfunction. Mol. Cell. Proteomics 15, 2576–2593 (2016).
Ishimura, R. et al. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 345, 455–459 (2014). This paper and ref. 41 identify mutations in mice that increase miscoding during translation and result in neurodegenerative phenotypes.
Lee, J. W. et al. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 443, 50–55 (2006).
Chu, J. et al. A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration. Proc. Natl Acad. Sci. USA 106, 2097–2103 (2009).
Triman, K. L. Mutational analysis of the ribosome. Adv. Genet. 58, 89–119 (2007).
Zaher, H. S. & Green, R. Hyperaccurate and error-prone ribosomes exploit distinct mechanisms during tRNA selection. Mol. Cell 39, 110–120 (2010).
Paredes, J. A. et al. Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast. BMC Biol. 10, 55 (2012).
Kalapis, D. et al. Evolution of robustness to protein mistranslation by accelerated protein turnover. PLoS Biol. 13, e1002291 (2015). This paper provides evidence of adaptation to proteotoxic stress through large chromosomal alterations and the genetic modification of protein-degradation systems.
Bengtson, M. H. & Joazeiro, C. A. Role of a ribosome-associated E3 ubiquitin ligase in protein quality control. Nature 467, 470–473 (2010).
Defenouillère, Q. et al. Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products. Proc. Natl Acad. Sci. USA 110, 5046–5051 (2013).
Pisareva, V. P., Skabkin, M. A., Hellen, C. U., Pestova, T. V. & Pisarev, A. V. Dissociation by Pelota, Hbs1 and ABCE1 of mammalian vacant 80S ribosomes and stalled elongation complexes. EMBO J. 30, 1804–1817 (2011).
Shao, S. & Hegde, R. S. Reconstitution of a minimal ribosome-associated ubiquitination pathway with purified factors. Mol. Cell 55, 880–890 (2014). This paper and ref. 50 reconstitute Ltn1-mediated RQC and establish the order of operations.
Shao, S., von der Malsburg, K. & Hegde, R. S. Listerin-dependent nascent protein ubiquitination relies on ribosome subunit dissociation. Mol. Cell 50, 637–648 (2013).
Shoemaker, C. J., Eyler, D. E. & Green, R. Dom34:Hbs1 promotes subunit dissociation and peptidyl-tRNA drop-off to initiate no-go decay. Science 330, 369–372 (2010).
Verma, R., Oania, R. S., Kolawa, N. J. & Deshaies, R. J. Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. eLife 2, e00308 (2013).
Brandman, O. & Hegde, R. S. Ribosome-associated protein quality control. Nature Struct. Mol. Biol. 23, 7–15 (2016).
Shen, P. S. et al. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science 347, 75–78 (2015). Refs 55, 57 and 59 identify the mechanism of RQC-mediated CAT-tail formation and demonstrate that defective tail formation suppresses the protein aggregation that results from RQC events.
Brandman, O. et al. A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell 151, 1042–1054 (2012).
Choe, Y. J. et al. Failure of RQC machinery causes protein aggregation and proteotoxic stress. Nature 531, 191–195 (2016).
Yang, J., Hao, X., Cao, X., Liu, B. & Nyström, T. Spatial sequestration and detoxification of Huntingtin by the ribosome quality control complex. eLife 5, e11792 (2016).
Yonashiro, R. et al. The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. eLife 5, e11794 (2016).
Higgins, R. et al. The unfolded protein response triggers site-specific regulatory ubiquitylation of 40S ribosomal proteins. Mol. Cell 59, 35–49 (2015).
Loayza-Puch, F. et al. Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature 530, 490–494 (2016).
Poortinga, G., Quinn, L. M. & Hannan, R. D. Targeting RNA polymerase I to treat MYC-driven cancer. Oncogene 34, 403–412 (2015).
Barna, M. et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456, 971–975 (2008). This paper demonstrates that a Myc-driven model of lymphoma can be suppressed by the haploinsufficiency of specific ribosomal genes.
Conn, C. S. & Qian, S. B. Nutrient signaling in protein homeostasis: an increase in quantity at the expense of quality. Sci. Signal. 6, ra24 (2013).
Mitsiades, N. et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc. Natl Acad. Sci. USA 99, 14374–14379 (2002).
Meiners, S. et al. Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of mammalian proteasomes. J. Biol. Chem. 278, 21517–21525 (2003).
Radhakrishnan, S. K. et al. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol. Cell 38, 17–28 (2010).
Ruggero, D. et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nature Med. 10, 484–486 (2004).
Avdulov, S. et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5, 553–563 (2004).
Lazaris-Karatzas, A., Montine, K. S. & Sonenberg, N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature 345, 544–547 (1990).
Hsieh, A. C. et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP–eIF4E. Cancer Cell 17, 249–261 (2010).
Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).
Truitt, M. L. et al. Differential requirements for eIF4E dose in normal development and cancer. Cell 162, 59–71 (2015). Refs 73 and 74 establish that tumorigenesis can be supressed in vivo by genetically limiting eIF4E.
Hsieh, A. C. et al. Cell type-specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors. Sci. Signal. 8, ra116 (2015).
Katz, W., Weinstein, B. & Solomon, F. Regulation of tubulin levels and microtubule assembly in Saccharomyces cerevisiae: consequences of altered tubulin gene copy number. Mol. Cell. Biol. 10, 5286–5294 (1990).
Weinstein, B. & Solomon, F. Phenotypic consequences of tubulin overproduction in Saccharomyces cerevisiae: differences between alpha-tubulin and beta-tubulin. Mol. Cell. Biol. 10, 5295–5304 (1990).
Li, G. W., Burkhardt, D., Gross, C. & Weissman, J. S. Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources. Cell 157, 624–635 (2014).
Torres, E. M. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317, 916–924 (2007). This study provided the first systematic analysis of both the effects of aneuploidy of intact chromosomes in yeast and the effects of an increased chromosome copy number on cell fitness.
Sheltzer, J. M. et al. Aneuploidy drives genomic instability in yeast. Science 333, 1026–1030 (2011).
Thorburn, R. R. et al. Aneuploid yeast strains exhibit defects in cell growth and passage through START. Mol. Biol. Cell 24, 1274–1289 (2013).
Blank, H. M., Sheltzer, J. M., Meehl, C. M. & Amon, A. Mitotic entry in the presence of DNA damage is a widespread property of aneuploidy in yeast. Mol. Biol. Cell 26, 1440–1451 (2015).
Dephoure, N. et al. Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. eLife 3, e03023 (2014). This paper provides a comprehensive proteomic and transcriptional analysis of yeast disomic strains, demonstrating that a subset of genes on disomes undergo dosage compensation through active mechanisms of turnover.
Tang, Y. C. & Amon, A. Gene copy-number alterations: a cost-benefit analysis. Cell 152, 394–405 (2013).
Bonney, M. E., Moriya, H. & Amon, A. Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes. Genes Dev. 29, 898–903 (2015).
Oromendia, A. B., Dodgson, S. E. & Amon, A. Aneuploidy causes proteotoxic stress in yeast. Genes Dev. 26, 2696–2708 (2012). This paper reveals that aneuploidy in yeast generates proteotoxic stress, which affects the ability of yeast to properly fold proteins that are already prone to misfolding.
Sheltzer, J. M., Torres, E. M., Dunham, M. J. & Amon, A. Transcriptional consequences of aneuploidy. Proc. Natl Acad. Sci. USA 109, 12644–12649 (2012).
Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).
Crosas, B. et al. Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 127, 1401–1413 (2006).
Torres, E. M. et al. Identification of aneuploidy-tolerating mutations. Cell 143, 71–83 (2010).
Tasaki, T., Sriram, S. M., Park, K. S. & Kwon, Y. T. The N-end rule pathway. Annu. Rev. Biochem. 81, 261–289 (2012).
Hwang, C. S., Shemorry, A. & Varshavsky, A. N-terminal acetylation of cellular proteins creates specific degradation signals. Science 327, 973–977 (2010).
Shemorry, A., Hwang, C. S. & Varshavsky, A. Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway. Mol. Cell 50, 540–551 (2013). This paper provides evidence for N-acetylation in the turnover of conserved oligomeric Golgi and anaphase-promoting complex proteins that are not properly assembled into their associated complexes.
Arnesen, T. et al. Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc. Natl Acad. Sci. USA 106, 8157–8162 (2009).
Van Damme, P. et al. NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation. PLoS Genet. 7, e1002169 (2011).
Scott, D. C., Monda, J. K., Bennett, E. J., Harper, J. W. & Schulman, B. A. N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex. Science 334, 674–678 (2011).
McClellan, A. J., Scott, M. D. & Frydman, J. Folding and quality control of the VHL tumor suppressor proceed through distinct chaperone pathways. Cell 121, 739–748 (2005).
Scazzari, M., Amm, I. & Wolf, D. H. Quality control of a cytoplasmic protein complex: chaperone motors and the ubiquitin-proteasome system govern the fate of orphan fatty acid synthase subunit Fas2 of yeast. J. Biol. Chem. 290, 4677–4687 (2015).
Schüller, H. J., Förtsch, B., Rautenstrauss, B., Wolf, D. H. & Schweizer, E. Differential proteolytic sensitivity of yeast fatty acid synthetase subunits α and β contributing to a balanced ratio of both fatty acid synthetase components. Eur. J. Biochem. 203, 607–614 (1992).
Kim, W. et al. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol. Cell 44, 325–340 (2011). This study provided the first large-scale analysis of the ubiquitin-modified proteome.
Warner, J. R. In the absence of ribosomal RNA synthesis, the ribosomal proteins of HeLa cells are synthesized normally and degraded rapidly. J. Mol. Biol. 115, 315–333 (1977).
Abovich, N., Gritz, L., Tung, L. & Rosbash, M. Effect of RP51 gene dosage alterations on ribosome synthesis in Saccharomyces cerevisiae. Mol. Cell. Biol. 5, 3429–3435 (1985).
Sung, M. K., Reitsma, J. M., Sweredoski, M. J., Hess, S. & Deshaies, R. J. Ribosomal proteins produced in excess are degraded by the ubiquitin–proteasome system. Mol. Biol. Cell http://dx.doi.org/10.1091/mbc.E16-05-0290 (2016).
Bursać, S. et al. Mutual protection of ribosomal proteins L5 and L11 from degradation is essential for p53 activation upon ribosomal biogenesis stress. Proc. Natl Acad. Sci. USA 109, 20467–20472 (2012).
Deisenroth, C. & Zhang, Y. Ribosome biogenesis surveillance: probing the ribosomal protein–Mdm2–p53 pathway. Oncogene 29, 4253–4260 (2010).
Hessa, T. et al. Protein targeting and degradation are coupled for elimination of mislocalized proteins. Nature 475, 394–397 (2011).
Shao, S. & Hegde, R. S. Target selection during protein quality control. Trends Biochem. Sci. 41, 124–137 (2016).
Wang, Q. et al. A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation. Mol. Cell 42, 758–770 (2011).
Rodrigo-Brenni, M. C., Gutierrez, E. & Hegde, R. S. Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Mol. Cell 55, 227–237 (2014).
Itakura, E. et al. Ubiquilins chaperone and triage mitochondrial membrane proteins for degradation. Mol. Cell 63, 21–33 (2016).
Wrobel, L. et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524, 485–488 (2015).
Mancias, J. D. & Kimmelman, A. C. Mechanisms of selective autophagy in normal physiology and cancer. J. Mol. Biol. 428, 1659–1680 (2016).
Stingele, S. et al. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol. Syst. Biol. 8, 608 (2012).
Santaguida, S., Vasile, E., White, E. & Amon, A. Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev. 29, 2010–2021 (2015). This paper demonstrates that autophagy is induced rapidly after chromosome mis-segregation in mammalian cells and that undigested proteins accumulate in lysosomes after delivery by autophagosomes.
Dou, Q. P. & Zonder, J. A. Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system. Curr. Cancer Drug Targets 14, 517–536 (2014).
Moreau, P. et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 374, 1621–1634 (2016).
San Miguel, J. Multiple myeloma: a model for scientific and clinical progress. Hematology Am. Soc. Hematol. Educ. Program 2014, 1–7 (2014).
Meyer, H., Bug, M. & Bremer, S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nature Cell Biol. 14, 117–123 (2012).
Christianson, J. C. & Ye, Y. Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nature Struct. Mol. Biol. 21, 325–335 (2014).
Zhou, H. J. et al. Discovery of a first-in-class, potent, selective, and orally bioavailable inhibitor of the p97 AAA ATPase (CB-5083). J. Med. Chem. 58, 9480–9497 (2015).
Anderson, D. J. et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28, 653–665 (2015). This paper identified inhibitors of the AAA-ATPase p97 and demonstrated their activity against cancer cells both in vitro and in xenograft experiments.
Donnelly, N., Passerini, V., Durrbaum, M., Stingele, S. & Storchova, Z. HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells. EMBO J. 33, 2374–2387 (2014).
Tang, Y. C., Williams, B. R., Siegel, J. J. & Amon, A. Identification of aneuploidy-selective antiproliferation compounds. Cell 144, 499–512 (2011).
Jhaveri, K., Taldone, T., Modi, S. & Chiosis, G. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim. Biophys. Acta 1823, 742–755 (2012).
Santagata, S. et al. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 341, 1238303 (2013).
Pelletier, J., Graff, J., Ruggero, D. & Sonenberg, N. Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res. 75, 250–263 (2015).
Drygin, D. et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 71, 1418–1430 (2011).
Devlin, J. R. et al. Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov. 6, 59–70 (2016).
Vilchez, D. et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 489, 304–308 (2012). Refs 128 and 129 establish that some populations of stem cells require lower rates of protein synthesis and show elevated capacities for protein degradation.
Signer, R. A., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49–54 (2014).
Cox, J. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell. Proteomics 13, 2513–2526 (2014).
The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
Vuckovic, D., Dagley, L. F., Purcell, A. W. & Emili, A. Membrane proteomics by high performance liquid chromatography-tandem mass spectrometry: analytical approaches and challenges. Proteomics 13, 404–423 (2013).
Marguerat, S. et al. Quantitative analysis of fission yeast transcriptomes and proteomes in proliferating and quiescent cells. Cell 151, 671–683 (2012).
Huttlin, E. L. et al. The BioPlex network: a systematic exploration of the human interactome. Cell 162, 425–440 (2015).
Kaganovich, D., Kopito, R. & Frydman, J. Misfolded proteins partition between two distinct quality control compartments. Nature 454, 1088–1095 (2008).
Escusa-Toret, S., Vonk, W. I. & Frydman, J. Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress. Nature Cell Biol. 15, 1231–1243 (2013).
Acknowledgements
J.W.H. is supported by grants from the US National Institutes of Health (AG011085, R37NS083524 and GM095567) and by grants from Biogen, Inc. E.J.B. is supported by grants from the National Institutes of Health (1DP2GM119132 and 2P50GM085764) and by a New Scholar in Aging award from The Ellison Medical Foundation (AG-NS-0902-12). We thank A. Amon at the Massachusetts Insitute of Technology for providing comments and insight during the preparation of this manuscript.
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Harper, J., Bennett, E. Proteome complexity and the forces that drive proteome imbalance. Nature 537, 328–338 (2016). https://doi.org/10.1038/nature19947
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DOI: https://doi.org/10.1038/nature19947
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