Nuclear protein quality control in yeast: The latest INQuiries
2022; Elsevier BV; Volume: 298; Issue: 8 Linguagem: Inglês
10.1016/j.jbc.2022.102199
ISSN1083-351X
AutoresArun Kumar, Veena Mathew, Peter C. Stirling,
Tópico(s)Endoplasmic Reticulum Stress and Disease
ResumoThe nucleus is a highly organized organelle with an intricate substructure of chromatin, RNAs, and proteins. This environment represents a challenge for maintaining protein quality control, since non-native proteins may interact inappropriately with other macromolecules and thus interfere with their function. Maintaining a healthy nuclear proteome becomes imperative during times of stress, such as upon DNA damage, heat shock, or starvation, when the proteome must be remodeled to effect cell survival. This is accomplished with the help of nuclear-specific chaperones, degradation pathways, and specialized structures known as protein quality control (PQC) sites that sequester proteins to help rapidly remodel the nuclear proteome. In this review, we focus on the current knowledge of PQC sites in Saccharomyces cerevisiae, particularly on a specialized nuclear PQC site called the intranuclear quality control site, a poorly understood nuclear inclusion that coordinates dynamic proteome triage decisions in yeast. The nucleus is a highly organized organelle with an intricate substructure of chromatin, RNAs, and proteins. This environment represents a challenge for maintaining protein quality control, since non-native proteins may interact inappropriately with other macromolecules and thus interfere with their function. Maintaining a healthy nuclear proteome becomes imperative during times of stress, such as upon DNA damage, heat shock, or starvation, when the proteome must be remodeled to effect cell survival. This is accomplished with the help of nuclear-specific chaperones, degradation pathways, and specialized structures known as protein quality control (PQC) sites that sequester proteins to help rapidly remodel the nuclear proteome. In this review, we focus on the current knowledge of PQC sites in Saccharomyces cerevisiae, particularly on a specialized nuclear PQC site called the intranuclear quality control site, a poorly understood nuclear inclusion that coordinates dynamic proteome triage decisions in yeast. Cells experiencing stress need to respond quickly. Be it external stressors such as DNA damage and heat shock or internal stressors such as genetic mutations, cells need to remodel their proteome to avoid accumulation of proteins that acquire non-native conformations. These misfolded proteins present short stretches of exposed hydrophobic regions that under normal conditions are buried inside the native conformation. These regions tend to be 'sticky' and if not acted on, could lead to the accumulation of toxic protein aggregates. Aggregated misfolded proteins present a physical roadblock and interfere with cellular trafficking and other processes in a gain of toxic function (1Woerner A.C. Frottin F. Hornburg D. Feng L.R. Meissner F. Patra M. et al.Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.Science. 2016; 351: 173-176Crossref PubMed Scopus (266) Google Scholar, 2Chou C.-C. Zhang Y. Umoh M.E. Vaughan S.W. Lorenzini I. Liu F. et al.TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD.Nat. Neurosci. 2018; 21: 228-239Crossref PubMed Scopus (264) Google Scholar). Aggregates also disrupt the molecular pathways that their constituents originally functioned in to create a loss-of-function that can perturb a variety of processes (3Winklhofer K.F. Tatzelt J. Haass C. The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases.EMBO J. 2008; 27: 336-349Crossref PubMed Scopus (281) Google Scholar). This overarching interference in cellular function is evident in neurodegenerative diseases such as Alzheimer's, ALS, and Parkinson's, which are pathologically associated with protein aggregation (4Soto C. Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases.Nat. Neurosci. 2018; 21: 1332-1340Crossref PubMed Scopus (439) Google Scholar, 5Ross C.A. Poirier M.A. Protein aggregation and neurodegenerative disease.Nat. Med. 2004; 10: S10-S17Crossref PubMed Scopus (2436) Google Scholar). It is therefore in the interest of the cell to maintain proteome homeostasis or proteostasis. This is achieved through a complex network of protein quality control (PQC) circuits that have been extensively studied and documented over the past 2 decades owing to their importance in maintaining a healthy proteome (6Enam C. Geffen Y. Ravid T. Gardner R.G. Protein quality control degradation in the nucleus.Annu. Rev. Biochem. 2018; 87: 725-749Crossref PubMed Scopus (43) Google Scholar, 7Franić D. Zubčić K. Boban M. Nuclear ubiquitin-proteasome pathways in proteostasis maintenance.Biomolecules. 2021; 11: 54Crossref PubMed Scopus (13) Google Scholar, 8Ciechanover A. Kwon Y.T. Protein quality control by molecular chaperones in neurodegeneration.Front. Neurosci. 2017; 11: 185Crossref PubMed Scopus (173) Google Scholar, 9Sontag E.M. Samant R.S. Frydman J. Mechanisms and functions of spatial protein quality control.Annu. Rev. Biochem. 2017; 86: 97-122Crossref PubMed Scopus (150) Google Scholar). At the core of these PQC circuits lie a class of proteins called molecular chaperones. Chaperones can be classified into various families of heat shock proteins (Hsps) such as sHsp (small HSP), Hsp40, Hsp60, Hsp70, Hsp90, and Hsp110 families and more (10Kim Y.E. Hipp M.S. Bracher A. Hayer-Hartl M. Hartl F.U. Molecular chaperone functions in protein folding and proteostasis.Annu. Rev. Biochem. 2013; 82: 323-355Crossref PubMed Scopus (966) Google Scholar, 11Saibil H. Chaperone machines for protein folding, unfolding and disaggregation.Nat. Rev. Mol. Cell Biol. 2013; 14: 630-642Crossref PubMed Scopus (645) Google Scholar). Many chaperones play constitutive roles in nascent protein folding, transport, and assembly, while others are strictly stress induced, responding to a variety of environmental insults. Many of these chaperones like CCT, Hsp70, and Hsp90 function as active 'foldases' utilizing ATP-dependent hydrolysis to promote folding, while others like Hsp40 and sHsps act as passive 'holdases' that protect and shield non-native surfaces. CCT actively encapsulates substrates in a cage-like structure, while Hsp70 and Hsp90 bind and release smaller domains to effect folding. Some other chaperones coordinate with protein degradation machinery to unfold and degrade target proteins. Chaperones like Btn2 and Hsp42 are known to help in protein aggregation and sequestration, while others like the Hsp40 Apj1 and Hsp110 help in protein disaggregation and refolding. Misfolded proteins, therefore, are constantly recognized, sequestered, refolded, or degraded to prevent accumulation of aggregates. Under stress, these circuits can be overwhelmed and ultimately result in protein aggregation. In such cases, the cell has to employ pathways specifically tasked with the role of clearing protein aggregates. Refolding, sequestration, and degradation represent the three fundamental triage decisions for non-native proteins and collectively define the idea of a PQC circuit . The process of PQC is at least partially organelle specific. Not only does each organelle contain a unique proteome but the mechanisms of protein import and export vary with respect to protein folding. For example, protein import to the endoplasmic reticulum (ER) or the mitochondria require that proteins be threaded through specialized pores that depend on chaperones (12Needham P.G. Guerriero C.J. Brodsky J.L. Chaperoning endoplasmic reticulum-associated degradation (ERAD) and protein conformational diseases.Cold Spring Harb. Perspect. Biol. 2019; 11: a033928Crossref PubMed Scopus (61) Google Scholar). Conversely, peroxisomes and the nucleus do not require protein unfolding for import (13Baker A. Lanyon-Hogg T. Warriner S.L. Peroxisome protein import: a complex journey.Biochem. Soc. Trans. 2016; 44: 783-789Crossref PubMed Scopus (27) Google Scholar). Perhaps, unsurprisingly, organelles can mount specific PQC responses. For example, the ER and the mitochondria both have specialized stress response machinery triggered in response to organellar stress (12Needham P.G. Guerriero C.J. Brodsky J.L. Chaperoning endoplasmic reticulum-associated degradation (ERAD) and protein conformational diseases.Cold Spring Harb. Perspect. Biol. 2019; 11: a033928Crossref PubMed Scopus (61) Google Scholar, 14Weidberg H. Amon A. MitoCPR-A surveillance pathway that protects mitochondria in response to protein import stress.Science. 2018; 360: eaan4146Crossref PubMed Scopus (164) Google Scholar). The nucleus is special with respect to PQC requirements because nuclear pores allow folded proteins and even large complexes in the native state to cross the nuclear membrane (15Kamenova I. Mukherjee P. Conic S. Mueller F. El-Saafin F. Bardot P. et al.Co-translational assembly of mammalian nuclear multisubunit complexes.Nat. Commun. 2019; 10: 1740Crossref PubMed Scopus (44) Google Scholar). Therefore, molecular chaperones associated with cotranslational protein folding should not strictly be required within the nucleus. Nevertheless, the Hsp70-40-110 system, the CCT chaperonin and its partner Prefoldin (PFD), Hsp90, and other chaperones are all present within the nucleus of yeast cells (16Shibata Y. Morimoto R.I. How the nucleus copes with proteotoxic stress.Curr. Biol. 2014; 24: R463-474Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). This suggests, despite importing ostensibly native proteins, that the folding, refolding, and protein complex assembly functions of chaperones are critically required in the nucleus under normal conditions. The nucleus is a complex organelle packed with chromatin, RNA, and protein that requires a stress-responsive PQC machinery to facilitate dynamic responses to environmental stimuli that require proteome remodeling (6Enam C. Geffen Y. Ravid T. Gardner R.G. Protein quality control degradation in the nucleus.Annu. Rev. Biochem. 2018; 87: 725-749Crossref PubMed Scopus (43) Google Scholar, 16Shibata Y. Morimoto R.I. How the nucleus copes with proteotoxic stress.Curr. Biol. 2014; 24: R463-474Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 17Jones R.D. Gardner R.G. Protein quality control in the nucleus.Curr. Opin. Cell Biol. 2016; 40: 81-89Crossref PubMed Scopus (22) Google Scholar). In this review, we focus on Saccharomyces cerevisiae to highlight recent advances in the field of nuclear PQC under different stressed conditions, the pathways involved, and its key players. We also assess the crosstalk between nuclear chaperones, protein degradation pathways, and spatiotemporal organization of sequestered protein compartments, with a core focus specifically on the compartment. When PQC homeostasis is first overwhelmed during stress, cells acutely sequester and organize non-native proteins into specialized compartments/aggregates/inclusions. This pillar of PQC is tightly regulated by chaperones that bind to misfolded proteins and sequester them at specific sites in the cell to facilitate refolding or degradation. This process of compartmentalization has several proposed advantages. Spatially organizing misfolded proteins not only reduces their cytotoxicity but also reduces the burden on other PQC pathways (18Ungelenk S. Moayed F. Ho C.-T. Grousl T. Scharf A. Mashaghi A. et al.Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding.Nat. Commun. 2016; 713673Crossref PubMed Scopus (109) Google Scholar, 19Wolfe K.J. Ren H.Y. Trepte P. Cyr D.M. The Hsp70/90 cochaperone, sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins.Mol. Biol. Cell. 2013; 24: 3588-3602Crossref PubMed Google Scholar). This in turn prevents PQC collapse and promotes stress recovery (20Ho C.-T. Grousl T. Shatz O. Jawed A. Ruger-Herreros C. Semmelink M. et al.Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis.Nat. Commun. 2019; 10: 4851Crossref PubMed Scopus (31) Google Scholar, 21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 22Escusa-Toret S. Vonk W.I.M. Frydman J. Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress.Nat. Cell Biol. 2013; 15: 1231-1243Crossref PubMed Scopus (214) Google Scholar). Furthermore, recruitment of degradation and refolding machineries to these sites could facilitate the clearance of misfolded proteins (explained later). Additionally, sequestration causes asymmetric inheritance of damaged proteins, resulting in inclusion-free daughter cells but contributing to replicative aging in mother cells (23Hill S.M. Hao X. Grönvall J. Spikings-Nordby S. Widlund P.O. Amen T. et al.Asymmetric inheritance of aggregated proteins and age reset in yeast are regulated by Vac17-dependent vacuolar functions.Cell Rep. 2016; 16: 826-838Abstract Full Text Full Text PDF PubMed Google Scholar, 24Saarikangas J. Barral Y. Protein aggregates are associated with replicative aging without compromising protein quality control.eLife. 2015; 4e06197Crossref PubMed Scopus (89) Google Scholar, 25Zhou C. Slaughter B.D. Unruh J.R. Guo F. Yu Z. Mickey K. et al.Organelle-based aggregation and retention of damaged proteins in asymmetrically dividing cells.Cell. 2014; 159: 530-542Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). In yeast, various PQC deposition sites have been described including three major inclusions: the insoluble protein deposit (IPOD), the juxtanuclear quality control site (JUNQ), and the intranuclear quality control site (INQ) (21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 26Kaganovich D. Kopito R. Frydman J. Misfolded proteins partition between two distinct quality control compartments.Nature. 2008; 454: 1088-1095Crossref PubMed Scopus (683) Google Scholar, 27Tkach J.M. Yimit A. Lee A.Y. Riffle M. Costanzo M. Jaschob D. et al.Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress.Nat. Cell Biol. 2012; 14: 966-976Crossref PubMed Scopus (323) Google Scholar, 28Miller S.B.M. Ho C.-T. Winkler J. Khokhrina M. Neuner A. Mohamed M.Y.H. et al.Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition.EMBO J. 2015; 34: 778-797Crossref PubMed Google Scholar). The IPOD is perivacuolar, adjacent to the preautophagosomal structure, and primarily made up of amyloidogenic proteins that are terminally aggregated, immobile and show a slow rate of diffusion with the cytosol (26Kaganovich D. Kopito R. Frydman J. Misfolded proteins partition between two distinct quality control compartments.Nature. 2008; 454: 1088-1095Crossref PubMed Scopus (683) Google Scholar) (Fig. 1). These include prions such as Rnq1, Sup35, and Ure2 and are reviewed as a PQC deposition site in detail elsewhere (29Rothe S. Prakash A. Tyedmers J. The Insoluble Protein Deposit (IPOD) in yeast.Front. Mol. Neurosci. 2018; 11: 237Crossref PubMed Scopus (15) Google Scholar). On the other hand, the JUNQ is associated with the nuclear envelope but is peripheral to it and resides outside the nucleus. Contrary to the IPOD, the JUNQ is highly dynamic in nature, soluble, and concentrates the 26S proteasome and disaggregation machinery and therefore acts as an active site for protein degradation and refolding (26Kaganovich D. Kopito R. Frydman J. Misfolded proteins partition between two distinct quality control compartments.Nature. 2008; 454: 1088-1095Crossref PubMed Scopus (683) Google Scholar). Partitioning between these two sites depends on the misfolded protein's ubiquitination state as blocking ubiquitination causes proteins to localize to IPOD instead of JUNQ and genetically engineering a ubiquitinated Rnq1-GFP localized to both the IPOD and JUNQ instead of only the IPOD (26Kaganovich D. Kopito R. Frydman J. Misfolded proteins partition between two distinct quality control compartments.Nature. 2008; 454: 1088-1095Crossref PubMed Scopus (683) Google Scholar). Other sites such as Q bodies, stress foci, and peripheral aggregates have also been found but have since been grouped together as CytoQ bodies that could potentially represent that same deposition site (22Escusa-Toret S. Vonk W.I.M. Frydman J. Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress.Nat. Cell Biol. 2013; 15: 1231-1243Crossref PubMed Scopus (214) Google Scholar, 28Miller S.B.M. Ho C.-T. Winkler J. Khokhrina M. Neuner A. Mohamed M.Y.H. et al.Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition.EMBO J. 2015; 34: 778-797Crossref PubMed Google Scholar, 30Spokoini R. Moldavski O. Nahmias Y. England J.L. Schuldiner M. Kaganovich D. Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast.Cell Rep. 2012; 2: 738-747Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 31Specht S. Miller S.B.M. Mogk A. Bukau B. Hsp42 is required for sequestration of protein aggregates into deposition sites in Saccharomyces cerevisiae.J. Cell Biol. 2011; 195: 617-629Crossref PubMed Scopus (185) Google Scholar). CytoQ bodies contain soluble misfolded proteins and undergo ATP-dependent coalescence that could represent the pathway that ultimately leads to JUNQ formation (9Sontag E.M. Samant R.S. Frydman J. Mechanisms and functions of spatial protein quality control.Annu. Rev. Biochem. 2017; 86: 97-122Crossref PubMed Scopus (150) Google Scholar, 22Escusa-Toret S. Vonk W.I.M. Frydman J. Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress.Nat. Cell Biol. 2013; 15: 1231-1243Crossref PubMed Scopus (214) Google Scholar). While the IPOD, JUNQ, and CytoQ reside in the cytoplasm, the INQ is present inside the nucleus and adjacent to the nucleolus (21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 27Tkach J.M. Yimit A. Lee A.Y. Riffle M. Costanzo M. Jaschob D. et al.Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress.Nat. Cell Biol. 2012; 14: 966-976Crossref PubMed Scopus (323) Google Scholar) (Fig. 1). Like JUNQ, the INQ is highly dynamic and contains the proteasome, disaggregation and degradation machineries, and is formed upon proteasome inhibition (21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 27Tkach J.M. Yimit A. Lee A.Y. Riffle M. Costanzo M. Jaschob D. et al.Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress.Nat. Cell Biol. 2012; 14: 966-976Crossref PubMed Scopus (323) Google Scholar, 28Miller S.B.M. Ho C.-T. Winkler J. Khokhrina M. Neuner A. Mohamed M.Y.H. et al.Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition.EMBO J. 2015; 34: 778-797Crossref PubMed Google Scholar, 32Mathew V. Tam A.S. Milbury K.L. Hofmann A.K. Hughes C.S. Morin G.B. et al.Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress.J. Cell Biol. 2017; 216: 4027-4040Crossref PubMed Scopus (6) Google Scholar). Since both the INQ and the JUNQ were discovered using the same model substrates, there has been an ongoing discussion about whether they represent the same or independent deposition sites. While this distinction needs to be investigated, recent studies have revealed some differences. Genotoxic stress induced via the alkylating agent methyl methanesulfonate (MMS) or oxidative damaging agent hydrogen peroxide induces the relocalization of several endogenous proteins to the INQ, whereas robust JUNQ formation is not seen (21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 27Tkach J.M. Yimit A. Lee A.Y. Riffle M. Costanzo M. Jaschob D. et al.Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress.Nat. Cell Biol. 2012; 14: 966-976Crossref PubMed Scopus (323) Google Scholar, 32Mathew V. Tam A.S. Milbury K.L. Hofmann A.K. Hughes C.S. Morin G.B. et al.Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress.J. Cell Biol. 2017; 216: 4027-4040Crossref PubMed Scopus (6) Google Scholar). This DNA damage–dependent relocalization to the INQ is not affected by actin or microtubule depolymerizing drugs like latrunculin B or nocodazole, suggesting that an intact cytoskeleton might not be a prerequisite for INQ deposition (21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar). Additionally, the INQ formation does not require ubiquitination, suggesting that the INQ and JUNQ might indeed be two distinct deposition sites separated by the nuclear envelope (28Miller S.B.M. Ho C.-T. Winkler J. Khokhrina M. Neuner A. Mohamed M.Y.H. et al.Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition.EMBO J. 2015; 34: 778-797Crossref PubMed Google Scholar). Since this review focuses on the nuclear PQC, going forward we will concern ourselves with the INQ as a sequestration site. Similar to other PQC sites, the INQ was first discovered using aggregation prone reporter proteins like the small ubiquitin-like modifier (SUMO)–conjugating E2 enzyme temperature-sensitive (ts) allele Ubc9-ts-GFP and von Hippen Lindau protein (VHL) and was shown to reside inside the nucleus using immunoelectron microscopy (28Miller S.B.M. Ho C.-T. Winkler J. Khokhrina M. Neuner A. Mohamed M.Y.H. et al.Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition.EMBO J. 2015; 34: 778-797Crossref PubMed Google Scholar). However, recent studies have found that many endogenous proteins are sequestered to the INQ upon genotoxic stress (Table 1) (21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 27Tkach J.M. Yimit A. Lee A.Y. Riffle M. Costanzo M. Jaschob D. et al.Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress.Nat. Cell Biol. 2012; 14: 966-976Crossref PubMed Scopus (323) Google Scholar, 32Mathew V. Tam A.S. Milbury K.L. Hofmann A.K. Hughes C.S. Morin G.B. et al.Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress.J. Cell Biol. 2017; 216: 4027-4040Crossref PubMed Scopus (6) Google Scholar, 33Saugar I. Jiménez-Martín A. Tercero J.A. Subnuclear relocalization of structure-specific endonucleases in response to DNA damage.Cell Rep. 2017; 20: 1553-1562Abstract Full Text Full Text PDF PubMed Google Scholar). Its formation can be induced by various DNA damaging agents such as MMS, ethyl methanesulfonate, hydroxyurea, hydrogen peroxide, UV radiation, and even upon heat shock coupled with proteasome inhibition (21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 32Mathew V. Tam A.S. Milbury K.L. Hofmann A.K. Hughes C.S. Morin G.B. et al.Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress.J. Cell Biol. 2017; 216: 4027-4040Crossref PubMed Scopus (6) Google Scholar, 33Saugar I. Jiménez-Martín A. Tercero J.A. Subnuclear relocalization of structure-specific endonucleases in response to DNA damage.Cell Rep. 2017; 20: 1553-1562Abstract Full Text Full Text PDF PubMed Google Scholar, 34den Brave F. Cairo L.V. Jagadeesan C. Ruger-Herreros C. Mogk A. Bukau B. et al.Chaperone-mediated protein disaggregation triggers proteolytic clearance of intra-nuclear protein inclusions.Cell Rep. 2020; 31107680Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Various efforts have gone into cataloging the proteins that relocalize to the INQ using mass spectrometric approaches. To date, 37 proteins have been found to relocalize to the INQ (Table 1). These proteins, or the INQ substrates, perform a diverse set of functions such as chromatin remodeling and transcription (Rpd3, Hos2, Cmr1), RNA splicing (Hsh155, Cdc40), or replication fork structure cleavage (Mus81-Mms4 and Slx1-Slx4). The INQ also harbors various chaperones and degradation machinery, including the AAA ATPase Cdc48, the disaggregase Hsp104, the sHsps Hsp42 and Btn2, the Hsp40 J-domain protein Apj1, the Slx5/8 ubiquitin ligase, and the proteasome, that can together decide the fate of the INQ substrates (Fig. 2A and Table 1).Table 1The INQ proteomeProteinsFunctionReferencesRpd3, Hos2, Arp6Chromatin remodeling(21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar)Mrc1, Cmr1aProteins containing one or more WD-40 repeats., Mus81, Mms4, Slx1, Slx4, Rad1Genome integrity(21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 33Saugar I. Jiménez-Martín A. Tercero J.A. Subnuclear relocalization of structure-specific endonucleases in response to DNA damage.Cell Rep. 2017; 20: 1553-1562Abstract Full Text Full Text PDF PubMed Google Scholar)Apc4aProteins containing one or more WD-40 repeats., Cdc20aProteins containing one or more WD-40 repeats., Cdc27Anaphase-promoting complex/Cyclosome(21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar)Hsh155, Cdc40aProteins containing one or more WD-40 repeats.Splicing(21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 32Mathew V. Tam A.S. Milbury K.L. Hofmann A.K. Hughes C.S. Morin G.B. et al.Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress.J. Cell Biol. 2017; 216: 4027-4040Crossref PubMed Scopus (6) Google Scholar)Pph3, Pph22, Fig4Phosphatases(21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar)Btn2, Apj1, Cdc48, Sis1, Hsp104, Slx8, Rpn11, Cct6Chaperones and degradation machinery(20Ho C.-T. Grousl T. Shatz O. Jawed A. Ruger-Herreros C. Semmelink M. et al.Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis.Nat. Commun. 2019; 10: 4851Crossref PubMed Scopus (31) Google Scholar, 21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar, 34den Brave F. Cairo L.V. Jagadeesan C. Ruger-Herreros C. Mogk A. Bukau B. et al.Chaperone-mediated protein disaggregation triggers proteolytic clearance of intra-nuclear protein inclusions.Cell Rep. 2020; 31107680Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 45Mathew V. Kumar A. Jiang Y.K. West K. Tam A.S. Stirling P.C. Cdc48 regulates intranuclear quality control sequestration of the Hsh155 splicing factor in budding yeast.J. Cell Sci. 2020; 133: jcs252551Crossref PubMed Scopus (2) Google Scholar)Gln1, Dug2aProteins containing one or more WD-40 repeats.Glutamine metabolism(21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar)Mkt1, Lst8, Emg1, Ylr126c, Rbd2, Dus3, Pal2, Qcr6, Mdh2Other(21Gallina I. Colding C. Henriksen P. Beli P. Nakamura K. Offman J. et al.Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.Nat. Commun. 2015; 6: 6533Crossref PubMed Scopus (58) Google Scholar)a Proteins containing one or more WD-40 repeats. Open table in a new tab INQ formation is governe
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