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• W2997779708 abstract "News & Views30 December 2019free access Shugoshin 2—a new guardian for heat shock transcription Amoldeep S Kainth orcid.org/0000-0002-8116-7747 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Rajyalakshmi Meduri Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Vickky Pandit Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Linda S Rubio Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author David S Gross [email protected] orcid.org/0000-0002-7957-8790 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Amoldeep S Kainth orcid.org/0000-0002-8116-7747 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Rajyalakshmi Meduri Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Vickky Pandit Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Linda S Rubio Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author David S Gross [email protected] orcid.org/0000-0002-7957-8790 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Search for more papers by this author Author Information Amoldeep S Kainth1, Rajyalakshmi Meduri1, Vickky Pandit1, Linda S Rubio1 and David S Gross1 1Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA EMBO J (2020)39:e104077https://doi.org/10.15252/embj.2019104077 See also: R Takii et al (December 2019) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Takii et al (2019) demonstrate in a recent issue of The EMBO Journal that the pericentromeric protein, SGO2, serves as a novel transcriptional coactivator of HSF1, contributing to PIC assembly and expression of Heat Shock Protein (HSP) genes. This finding highlights repurposing of a protein with a nuclear function to drive transcription of proteotoxic stress machinery genes. Central to eukaryotic transcriptional control are two binding reactions: (i) binding of a gene-specific transcription factor (GSTF) to a cognate DNA sequence via its DNA-binding domain (DBD); and (ii) interaction of the DNA-bound GSTF with coactivators and general transcription factors via one or more transactivation domains. Epitomizing this paradigm is the eukaryotic transcriptional response to proteotoxic stress. In response to such stress, Heat Shock Factor 1 (HSF1) binds to its cognate genomic sites, termed heat shock elements (HSEs; typically located in a proximal or distal enhancer), in a phosphorylated and trimeric form. Multiple coactivator proteins then interact with DNA-bound HSF1, principally through its activation domain(s) (Fig 1A). These coactivators enhance or facilitate the HSF1-driven transcriptional program by a variety of mechanisms including recruitment and assembly of the transcription initiation complex, recruitment of chromatin modification and remodeling complexes, and formation of chromatin loops. Therefore, like many other GSTFs, HSF1 is highly dependent upon coactivators to drive the transcription of its target genes. In the case of HSF1, this permits it to carry out its cytoprotective function in the face of acutely stressful conditions. As HSF1 is implicated in cancer and neurodegeneration (Gomez-Pastor et al, 2018), identification and characterization of its coactivators may provide novel molecular handles to modulate its activity. In a recent issue of The EMBO Journal, Takii et al (2019) report the identification of Shugoshin2 (SGO2) as a novel coactivator of HSF1. SGO2 is a pericentromeric protein that associates with cohesin at centromeres and regulates chromosomal segregation during meiosis (Gutierrez-Caballero et al, 2012). Using an evolutionary approach to compare HSF1 paralogs from different vertebrate species, the authors performed an unbiased search to identify HSF1-associated factors in mouse embryonic fibroblast cells. In addition to finding known cofactors of HSF1, the study reports a set of novel coactivators. Focusing on one such factor, SGO2, the authors find that its knockdown leads to a reduction in the heat shock-induced mRNA levels of canonical HSF1 targets. Further characterization showed that HSF1 phosphorylated at Ser326 recruits SGO2 to the mouse HSP70 promoter. A detailed domain dissection of SGO2 showed that it interacts with HSF1 and Pol II using two independent regions. This bipartite interaction facilitates heat shock-dependent Pol II recruitment to HSP gene promoters, unveiling the functional importance of SGO2 in HSF1-mediated transcriptional activation (Fig 1B). Figure 1. The pericentromeric protein Shugoshin 2 is coopted by HSF1 to activate transcription under proteotoxic stress(A) Stress-activated HSF1 binds to a heat shock element (HSE) in a phosphorylated, trimeric form. DNA-bound HSF1 interacts with a variety of coactivators that facilitate the HSF1-driven transcription program. Shown in the magnified boxes are structural depictions of HSF1 coactivators involved in chromatin access, recruitment/assembly of the transcription initiation complex, and productive RNA Pol II elongation, leading to activation of HSF1 target genes. (B) Takii et al demonstrated in a recent issue of The EMBO Journal that the pericentromeric protein, SGO2, serves as a novel coactivator of HSF1 in mouse cells. SGO2 is recruited by S326-phosphorylated HSF1 to the promoter and 5′-pausing region of HSP genes, where it in turn recruits hypophosphorylated Pol II. In combination with Mediator (and other coactivators), a functional initiation complex is assembled and Pol II enters productive elongation upon phosphorylation of its CTD. Download figure Download PowerPoint This finding establishes SGO2 as an important coactivator of HSF1 and provides an opportunity to compare and contrast previously identified HSF1 coactivators. For example, the multisubunit Mediator has been identified as an HSF1 coactivator in budding yeast and Drosophila (Park et al, 2001; Kim & Gross, 2013; Anandhakumar et al, 2016). The unbiased approach of Takii et al (2019) identified no fewer than 14 subunits of Mediator that assembled on the HSP70 promoter in an HSF1- and HSE-dependent manner in an in vitro reconstitution. Similar to SGO2, Mediator makes bipartite contacts with HSF1 and Pol II employing different subunits from its tail, middle, and head modules. Heat Shock Factor 1 not only employs pre-existing nuclear proteins but also facilitates nuclear import of a mitochondrial protein, SSBP1, that translocates into the nucleus upon stress in an HSF1-dependent manner and acts as a coactivator by recruiting BRG1 (the ATPase subunit of SWI/SNF) to HSF1-regulated genes (Tan et al, 2015). In addition, HSF1 employs the coactivators GCN5 and Tip60 for transcription of long non-coding RNAs at the pericentric heterochromatic 9q12 region of mouse cells (Col et al, 2017). This interaction facilitates recruitment and function of the p300 histone acetyltransferase for expression of satellite III lncRNA. Heat Shock Factor 1 also enlists cofactors to enable its binding to chromatin. Nakai and colleagues have shown that replication protein A (RPA), whose best known activity is the binding of single-stranded DNA at replication forks or at DNA undergoing repair, is recruited by HSF1 through its interaction with the winged region of HSF1's DBD. RPA maintains a nucleosome-free region at the HSP70 promoter, an activity assisted by the transcription-coupled histone chaperone FACT (Fujimoto et al, 2012). While the aforementioned coactivators are typically shown to be involved in heat shock-mediated activation of HSF1, PGC1α, a regulator of energy metabolism, facilitates HSF1-mediated activation of chaperones during cold shock in brown and inguinal fat in mice (Xu et al, 2016). Intriguingly, PGC1α represses HSF1 in mouse hepatocytes, indicating a cell type-specific function for this HSF1-coactivator interaction (Minsky & Roeder, 2015). We note that although most of the above-mentioned findings arise from the study of specific coactivators, it is highly probable that their roles are not mutually exclusive. In that vein, SAGA and Mediator are recruited to Hsf1-regulated genes in a mutually independent fashion in budding yeast (Anandhakumar et al, 2016). In contrast, (Takii et al, 2019) show that in mouse cells, occupancy of Mediator is reduced upon SGO2 knockdown, implying a potential role for SGO2 in the stable association of Mediator with HSF1 regulatory regions. Taken together, it is evident that a variety of coactivators play important roles in the HSF1 transcriptional program. Is HSF1 unusual in its deployment of novel coactivators? The answer is no; over 400 coregulators of transcription have thus far been identified. Among the best studied is a distinctive family of coactivators, the steroid response coactivators (SRC1, 2, 3), that bind nuclear hormone receptors. SRCs bind nuclear hormone receptors in a ligand-dependent fashion and serve to recruit “secondary coactivators”, many of which are also recruited by HSF1: histone acetyl transferases such as CBP/p300, GCN5, and Tip60; histone methyl transferases such as MLL; and chromatin remodeling enzymes such as SWI/SNF (Johnson & O'Malley, 2012). And as is the case with SGO2, the well-studied and multifaceted protein β-catenin can under certain circumstances be coopted into serving as a transcriptional coactivator, in this case for TCF (T cell factor) and LEF-1 (lymphoid enhancing factor), as part of β-catenin's role in Wnt signaling (Cadigan & Waterman, 2012). How do different coactivators interplay with each other? Is there cell-type specificity of coactivators? What role do coactivators play in the HSF1-driven 3D architecture of HSP genes (Chowdhary et al, 2019)? What role do coactivators play in HSF1's activity in disease states? While answers to these questions remain unknown, they may hold an important clue into how one of the most conserved transcriptional programs in the eukaryotic kingdom is modulated. References Anandhakumar J, Moustafa YW, Chowdhary S, Kainth AS, Gross DS (2016) Evidence for multiple Mediator complexes in yeast independently recruited by activated Heat Shock Factor. Mol Cell Biol 36: 1943–1960CrossrefPubMedWeb of Science®Google Scholar Cadigan KM, Waterman ML (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 4: a007906CrossrefCASPubMedWeb of Science®Google Scholar Chowdhary S, Kainth AS, Pincus D, Gross DS (2019) Heat Shock Factor 1 drives intergenic association of its target gene loci upon heat shock. Cell Rep 26: 18–28.e5CrossrefCASPubMedWeb of Science®Google Scholar Col E, Hoghoughi N, Dufour S, Penin J, Koskas S, Faure V, Ouzounova M, Hernandez-Vargash H, Reynoird N, Daujat S et al (2017) Bromodomain factors of BET family are new essential actors of pericentric heterochromatin transcriptional activation in response to heat shock. Sci Rep 7: 5418CrossrefPubMedWeb of Science®Google Scholar Fujimoto M, Takaki E, Takii R, Tan K, Prakasam R, Hayashida N, Iemura S, Natsume T, Nakai A (2012) RPA assists HSF1 access to nucleosomal DNA by recruiting histone chaperone FACT. Mol Cell 48: 182–194CrossrefCASPubMedWeb of Science®Google Scholar Gomez-Pastor R, Burchfiel ET, Thiele DJ (2018) Regulation of heat shock transcription factors and their roles in physiology and disease. Nat Rev Mol Cell Biol 19: 4–19CrossrefCASPubMedWeb of Science®Google Scholar Gutierrez-Caballero C, Cebollero LR, Pendas AM (2012) Shugoshins: from protectors of cohesion to versatile adaptors at the centromere. Trends Genet 28: 351–360CrossrefCASPubMedWeb of Science®Google Scholar Johnson AB, O'Malley BW (2012) Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy. Mol Cell Endocrinol 348: 430–439CrossrefCASPubMedWeb of Science®Google Scholar Kim S, Gross DS (2013) Mediator recruitment to heat shock genes requires dual Hsf1 activation domains and Mediator tail subunits Med15 and Med16. J Biol Chem 288: 12197–12213CrossrefCASPubMedWeb of Science®Google Scholar Minsky N, Roeder RG (2015) Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC1α. Proc Natl Acad Sci USA 112: E5669–E5678CrossrefCASPubMedWeb of Science®Google Scholar Park JM, Werner J, Kim JM, Lis JT, Kim Y-J (2001) Mediator, not holoenzyme, is directly recruited to the heat shock promoter by HSF upon heat shock. Mol Cell 8: 9–19CrossrefCASPubMedWeb of Science®Google Scholar Takii R, Fujimoto M, Matsumoto M, Srivastava P, Katiyar A, Nakayama KI, Nakai A (2019) The pericentromeric protein shugoshin 2 cooperates with HSF1 in heat shock response and RNA Pol II recruitment. EMBO J 38: e102566Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Tan K, Fujimoto M, Takii R, Takaki E, Hayashida N, Nakai A (2015) Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity. Nat Commun 6: 6580CrossrefCASPubMedWeb of Science®Google Scholar Xu L, Ma X, Bagattin A, Mueller E (2016) The transcriptional coactivator PGC1α protects against hyperthermic stress via cooperation with the heat shock factor HSF1. Cell Death Dis 7: e2102CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 39,Issue 2,15 January 2020This month's cover highlights the article ESCRT machinery mediates selective microautophagy of endoplasmic reticulum in yeast. by Jasmin A. Sch�fer, Sebastian Schuck and colleagues. Stack it, bend it, eat it ‐ a multilamellar ER whorl imported into the yeast lysosome by microautophagy (Scientific image by Jasmin A. Sch�fer and Charlotta Funaya, Heidelberg University.) Volume 39Issue 215 January 2020In this issue FiguresReferencesRelatedDetailsLoading ..." @default.
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