ERK-mediated phosphorylation of BIS regulates nuclear translocation of HSF1 under oxidative stress

Kim, Hye Yun; Kim, Yong-Sam; Yun, Hye Hyeon; Im, Chang‐Nim; Ko, Jeong–Heon; Lee, Jeong-Hwa

doi:10.1038/emm.2016.84

Cited by 19 publications

(14 citation statements)

References 55 publications

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“…In principle, HSPB8 and BAG3 could affect p62 levels via multiple mechanisms, including transcription and autophagic degradation. For instance, evidence suggests that BAG3 can modulate transcription factors [i.e., HSF1 (77) and Nrf2 (the present study)], which are reported to regulate p62 levels (33,34,78,79). Our preliminary results suggest that p62 mRNA levels are reduced in HSPB8-and BAG3-depleted cells.…”

Section: Discussionsupporting

confidence: 60%

HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

et al. 2018

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BCL2-associated athanogene (BAG)-3 is viewed as a platform that would physically and functionally link distinct classes of molecular chaperones of the heat shock protein (HSP) family for the stabilization and clearance of damaged proteins. In this study, we show that HSPB8, a member of the small heat shock protein subfamily, cooperates with BAG3 to coordinate the sequestration of harmful proteins and the cellular adaptive response upon proteasome inhibition. Silencing of HSPB8, like depletion of BAG3, inhibited targeting of ubiquitinated proteins to the juxtanuclear aggresome, a mammalian system of spatial quality control. However, aggresome targeting was restored in BAG3-depleted cells by a mutant BAG3 defective in HSPB8 binding, uncoupling HSPB8 function from its binding to BAG3. Depletion of HSPB8 impaired formation of ubiquitinated microaggregates in an early phase and interfered with accurate modifications of the stress sensor p62/sequestosome (SQSTM)-1. This impairment correlated with decreased coupling of BAG3 to p62/SQSTM1 in response to stress, hindering Kelch-like ECH-associated protein (KEAP)-1 sequestration and stabilization of nuclear factor E2-related factor (Nrf)-2, an important arm of the antioxidant defense. Notably, the myopathy-associated mutation of BAG3 (P209L), which lies within the HSPB8-binding motif, deregulated the association between BAG3 and p62/SQSTM1 and the KEAP1-Nrf2 signaling axis. Together, our findings support a so-far-unrecognized role for the HSPB8-BAG3 connection in mounting of an efficient stress response, which may be involved in BAG3-related human diseases.-Guilbert, S. M., Lambert, H., Rodrigue, M.-A., Fuchs, M., Landry, J., Lavoie, J. N. HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency.

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Section: Discussionsupporting

confidence: 60%

HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

et al. 2018

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“…BIS is a transcriptional target of HSF1 and also has been shown to interact with HSF1 in proteomic analyses [ 7 , 8 , 9 , 23 ]. Recently, we demonstrated that BIS is phosphorylated upon oxidative stress via ERK activation and that the deletion of phosphorylation sites in the protein stretch encoded by exon 3 attenuated the translocation of HSF1 upon oxidative stress [ 18 ]. Moreover, the splicing factor SF3B1 was shown to affect the activation of HSF1 via the mRNA level [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we identified the induction of BIS phosphorylation at Thr285 and Ser289 in the protein stretch encoded by exon 3 under oxidative stress occurred in an ERK-dependent manner, which was important for releasing HSF1 into the nucleus [ 18 ]. However, heat shock stress did not induce phosphorylation of the BIS protein even though BIS was also shown to be involved in the shuttling of HSF1 under heat stress [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cell protein extracts were prepared, and a Western blotting analysis was carried out as previously described, following standard procedures [ 18 , 19 ]. Briefly, whole-cell lysates were prepared in RIPA buffer (50 mM Tris, 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, and pH 7.5) with a protease inhibitor cocktail (Roche, Basel, Switzerland) and phosphate inhibitor (Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

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SRSF3 Is a Critical Requirement for Inclusion of Exon 3 of BIS Pre-mRNA

Baek

Yun

Jung

et al. 2020

Cells

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BCL-2 interacting cell death suppressor (BIS), also known as BAG3, is a multifunctional protein. Aberrant expression and mutation of BIS have been implicated in cancers and myopathy. However, there have only been a few studies on the splicing of BIS pre-mRNA. In the present study, through RT-PCR and sequencing in various cell lines and mouse tissues, we identified for the first time the presence of BIS mRNA isomers in which exon 3 or exons 2–3 are skipped. We also demonstrated that the depletion of SRSF3 promoted the skipping of exon 3 of BIS pre-mRNA in endogenous BIS and the GFP-BIS minigene. SRSF3 specifically interacts with the putative binding sites in exon 3, in which deletion promoted the skipping of exon 3 in the GFP-BIS minigene, which was comparable to the effect of SRSF knockdown. Even though acceleration of exon 3 skipping was not observed in response to various stimuli, SRSF3 depletion, accompanied by the production of a truncated BIS protein, inhibited the nuclear translocation of HSF1, which was restored by the wild-type BIS, not by exon 3-depleted BIS. Therefore, our results suggested that the maintenance of SRSF3 levels and subsequent preservation of the intact BIS protein is an important factor in modulating HSF1 localization upon cellular stress.

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“…Supporting this possibility, the effect of BIS on nuclear translocation of HSF1 has been previously reported. For example, oxidative stress-induced phosphorylation of BIS protein weakens its binding ability to HSF1, thereby accelerating its nuclear translocation in A172 cells [ 37 ]. BIS was also shown to co-translocate into the nucleus with HSF1 upon heat shock stress in HeLa cells [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of BIS depletion on HSF1-dependent transcriptional activation in A549 non-small cell lung cancer cells

Yun

Baek

Seo

et al. 2018

Korean J Physiol Pharmacol

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The expression of BCL-2 interacting cell death suppressor (BIS), an anti-stress or anti-apoptotic protein, has been shown to be regulated at the transcriptional level by heat shock factor 1 (HSF1) upon various stresses. Recently, HSF1 was also shown to bind to BIS, but the significance of these protein-protein interactions on HSF1 activity has not been fully defined. In the present study, we observed that complete depletion of BIS using a CRISPR/Cas9 system in A549 non-small cell lung cancer did not affect the induction of heat shock protein (HSP) 70 and HSP27 mRNAs under various stress conditions such as heat shock, proteotoxic stress, and oxidative stress. The lack of a functional association of BIS with HSF1 activity was also demonstrated by transient downregulation of BIS by siRNA in A549 and U87 glioblastoma cells. Endogenous BIS mRNA levels were significantly suppressed in BIS knockout (KO) A549 cells compared to BIS wild type (WT) A549 cells at the constitutive and inducible levels. The promoter activities of BIS and HSP70 as well as the degradation rate of BIS mRNA were not influenced by depletion of BIS. In addition, the expression levels of the mutant BIS construct, in which 14 bp were deleted as in BIS-KO A549 cells, were not different from those of the WT BIS construct, indicating that mRNA stability was not the mechanism for autoregulation of BIS. Our results suggested that BIS was not required for HSF1 activity, but was required for its own expression, which involved an HSF1-independent pathway.

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ERK-mediated phosphorylation of BIS regulates nuclear translocation of HSF1 under oxidative stress

Cited by 19 publications

References 55 publications

HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

SRSF3 Is a Critical Requirement for Inclusion of Exon 3 of BIS Pre-mRNA

Effect of BIS depletion on HSF1-dependent transcriptional activation in A549 non-small cell lung cancer cells

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