Shugoshin 2—a new guardian for heat shock transcription

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.

New work finds heat response master regulator HSF1 co‐opting a pericentromeric protein for transcriptional activation and rescue of cells from proteotoxic stress.

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.

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.

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).

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.

The EMBO Journal (2020) 39: e104077