Hop depletion reduces HSF1 levels and activity and coincides with reduced stress resilience

Chakraborty, Abantika; Edkins, Adrienne L.

doi:10.1016/j.bbrc.2020.04.072

Cited by 10 publications

(5 citation statements)

References 37 publications

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“…Furthermore, Hop levels drop in the aging brain, and aging is correlated with reduced proteasomal and chaperoning activity 67,81 . Since the absence of Hop generates a mixed outcome in different experimental models [32][33][34][35][82][83][84] , tissue-and cell typespecific functions of Hop for the maintenance of proteostasis should be further studied.…”

Section: Xrcc6 Xr Xr X X P58 P58 No O N N a A A A A A A A A A A A A Amentioning

confidence: 99%

The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation

et al. 2020

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Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a number of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knock-out cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70-Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures the proteostatic equilibrium. Thus, cells may act on the level and/or activity of Hop to shift the proteostatic balance between folding and degradation.

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Section: Xrcc6 Xr Xr X X P58 P58 No O N N a A A A A A A A A A A A A Amentioning

confidence: 99%

The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation

et al. 2020

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“…One can imagine that the relatively hyperactive Hsp70–Hsp90 binary complex in the absence of Hop might be protective upon heat shock. In contrast, the knockdown of Hop in human HEK293T cells with a doxycycline-inducible system was reported to reduce viability under basal and heat-shock conditions [ 124 ]. These differences between the knockout and knockdown models are striking and may be explained by the long-term adaptation to the Hop depletion during the clonal establishment of Hop knockout cells.…”

Section: Phenotypes Of Hop Mutants In Eukaryotic Organismsmentioning

confidence: 99%

The Hsp70–Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration

Bhattacharya

Picard

2021

Cell. Mol. Life Sci.

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The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate (“client”) transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.

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“…Under such conditions, the high accumulation of misfolded proteins force the chaperones to release the HSF1, which now accumulates in the nucleus and binds the promoters of its responsive genes, allowing the onset of the HSR (Anckar and Sistonen, 2011;Masser et al, 2020;Voellmy and Boellmann, 2007). Remarkably, it has been recently reported that the nuclear accumulation of HSF1 is reduced by depletion of HOP in mammalian cells, which indicates that, in addition to the HSP70 and the HSP90 chaperones, the co-chaperone HOP could be also involved in the tritation of HSF1 in these specific eukaryotes (Chakraborty and Edkins, 2020).…”

Section: Hsr Is Highly Altered In Response To Warm Temperatures In Th...mentioning

confidence: 99%

The HSFA1a is stabilized by the co-chaperone HSP70-HSP90 organizing protein HOP in Arabidopsis

Toribio,

Navarro,

Castellano

2024

Preprint

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Living organisms have the capacity to sense and respond to environmental stimuli, including warm conditions. Upon the increase of temperature, eukaryotic cells promote the onset of a universal transcriptional response called the heat stress response (HSR). HSR is triggered by the activation of the heat shock factor 1 (HSF1), whose activity is highly regulated in all eukaryotes. A common process of HSFA1 regulation involves its binding to HSP70 and HSP90 chaperones. However, the effect of this binding differs among eukaryotes and is not fully elucidated in plants. Moreover, the role of chaperone auxiliary proteins, such as HOP, in HSF1 regulation remains unknown. Here, we show that HOP is involved in the folding and stabilization of the HSFA1a and is required for the onset of the HSR during thermomorphogenesis in Arabidopsis. Our results demonstrate that the members of the AtHOP family bind in vivo to the HSFA1a and that the expression of multiple genes involved in the HSR, including numerous HSFA1a-responsive genes, is altered in the hop1 hop2 hop3 mutant under warm temperature. HOP is not involved in the subcellular localization of the AtHSFA1a. Instead, HSFA1a is accumulated at lower levels in the hop1 hop2 hop3 mutant while control levels are recovered in the presence of the proteasome inhibitor MG132 or the synthetic chaperone TUDCA. This uncovers the HSFA1a as a new client of HOP in plants and reveals the participation of HOP in HSFA1a stability, expanding the notorious function of the co-chaperone HOP in thermomorphogenesis.

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Hop depletion reduces HSF1 levels and activity and coincides with reduced stress resilience

Cited by 10 publications

References 37 publications

The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation

The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation

The Hsp70–Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration

The HSFA1a is stabilized by the co-chaperone HSP70-HSP90 organizing protein HOP in Arabidopsis

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