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RNF20/40-mediated eEF1BδL monoubiquitylation stimulates transcription of heat shock-responsive genes.

ABSTRACT: RNF20/40 E3 ubiquitin ligase-mediated histone H2B monoubiquitylation plays important roles in many cellular processes, including transcriptional regulation. However, the multiple defects observed in RNF20-depleted cells suggest additional ubiquitylation targets of RNF20/40 beyond histone H2B. Here, using biochemically defined assays employing purified factors and cell-based analyses, we demonstrate that RNF20/40, in conjunction with its cognate E2 ubiquitin-conjugating enzyme RAD6, monoubiquitylates lysine 381 of eEF1BδL, a heat shock transcription factor. Notably, monoubiquitylation of eEF1BδL increases eEF1BδL accumulation and potentiates recruitment of p-TEFb to the promoter regions of heat shock-responsive genes, leading to enhanced transcription of these genes. We further demonstrate that cooperative physical interactions among eEF1BδL, RNF20/40, and HSF1 synergistically promote expression of heat shock-responsive genes. In addition to identifying eEF1BδL as a novel ubiquitylation target of RNF20/40 and elucidating its function, we provide a molecular mechanism for the cooperative function of distinct transcription factors in heat shock-responsive gene transcription.

SUBMITTER: In S

PROVIDER: S-EPMC6451099 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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RNF20/40-mediated eEF1BδL monoubiquitylation stimulates transcription of heat shock-responsive genes.

In Suna S Kim Yong-In YI Lee J Eugene JE Kim Jaehoon J

Nucleic acids research 20190401 6

RNF20/40 E3 ubiquitin ligase-mediated histone H2B monoubiquitylation plays important roles in many cellular processes, including transcriptional regulation. However, the multiple defects observed in RNF20-depleted cells suggest additional ubiquitylation targets of RNF20/40 beyond histone H2B. Here, using biochemically defined assays employing purified factors and cell-based analyses, we demonstrate that RNF20/40, in conjunction with its cognate E2 ubiquitin-conjugating enzyme RAD6, monoubiquityl ...[more]

PMID: 30649429

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Project description:BackgroundRegulation of transcriptional activity of heat shock factor-1 (HSF1) is widely thought to be the main point of control for heat shock protein (Hsp) expression.ResultsGlutamine increases Hsf1 gene transcription in a C/EBPβ-dependent manner and up-regulates HSF1 activity.ConclusionGlutamine is an activator for both HSF1 expression and transactivation.SignificanceGlutamine-induced HSF1 expression provides a novel mechanistic frame for HSF1-Hsp axis regulation. Heat shock transcription factor-1 (HSF1) is the master regulator for cytoprotective heat shock protein (Hsp) expression. It is widely thought that HSF1 expression is non-inducible, and thus the key control point of Hsp expression is regulation of the transactivation activity of HSF1. How HSF1 expression is regulated remains unknown. Herein we demonstrate that glutamine (Gln), a preferred fuel substrate for the gut, enhanced Hsp expression both in rat colonic epithelium in vivo and in cultured non-transformed young adult mouse colonic epithelial cells. This was associated with up-regulation of the transactivation activity of HSF1 via increased HSF1 trimerization, nuclear localization, DNA binding, and relative abundance of activating phosphorylation at Ser-230 of HSF1. More intriguingly, Gln enhanced HSF1 protein and mRNA expression and Hsf1 gene promoter activity. Within the -281/-200 region of the Hsf1 promoter, deletion of the putative CCAAT enhancer-binding protein (C/EBP) binding site abolished the HSF1 response to Gln. C/EBPβ was further shown to bind to this 82-bp sequence both in vitro and in vivo. Gln availability strikingly altered the ratio of C/EBPβ inhibitory and active isoforms, i.e. liver-enriched inhibitory protein and liver-enriched activating protein. Liver-enriched inhibitory protein and liver-enriched activating protein were further shown to be an independent repressor and activator, respectively, for Hsf1 gene transcription, and the relative abundance of these two C/EBPβ isoforms was demonstrated to determine Hsf1 transcription. We show for the first time that Gln not only enhances the transactivation of HSF1 but also induces Hsf1 expression by activating its transcription in a C/EBPβ-dependent manner.

Project description:BackgroundHeat shock transcription factors (HSFs) play crucial roles in the development of malignancies. However, the specific roles of HSFs in hepatocellular carcinoma (HCC) have yet to be fully elucidated.AimsTo explore the involvement of the HSF family, particularly HSF1, in the progression and prognosis of HCC.Materials & methodsWe conducted a thorough analysis of HSF expression and copy number variations across various cancer datasets. Specifically focusing on HSF1, we examined its expression levels and prognostic implications in HCC. In vitro and in vivo experiments were carried out to evaluate the impact of HSF1 on liver cancer cell proliferation. Additionally, we utilized CUT&Tag, H3K27 acetylation enrichment, and RNA sequencing (RNA-seq) to investigate the super-enhancer (SE) regulatory landscapes of HSF1 in liver cancer cell lines.ResultsHSF1 expression is elevated in HCC and is linked to poor prognosis in several datasets. HSF1 stimulates liver cancer cell proliferation both in vitro and in vivo, partly through modulation of H3K27ac levels, influencing enhancer distribution. Mechanistically, our findings demonstrate that HSF1 transcriptionally activates MYCN expression by binding to its promoter and SE elements, thereby promoting liver cancer cell proliferation. Moreover, increased MYCN expression was detected in HCC tumors and correlated with unfavorable patient outcomes.DiscussionOur study sheds light on previously unexplored aspects of HSF1 biology, identifying it as a transcription factor capable of shaping the epigenetic landscape in the context of HCC. Given HSF1's potential as an epigenetic regulator, targeting the HSF1-MYCN axis could open up new therapeutic possibilities for HCC treatment.ConclusionThe HSF1-MYCN axis constitutes a transcription-dependent regulatory mechanism that may function as both a prognostic indicator and a promising therapeutic target in liver cancer. Further exploration of this axis could yield valuable insights into novel treatment strategies for HCC.

Dataset Information

RNF20/40-mediated eEF1BδL monoubiquitylation stimulates transcription of heat shock-responsive genes.

Publications

RNF20/40-mediated eEF1BδL monoubiquitylation stimulates transcription of heat shock-responsive genes.

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