Hsp90 and its co‐chaperone Sti1 control TDP‐43 misfolding and toxicity

Lin, Lilian Tsai-Wei; Razzaq, Abdul; Gregorio, Sonja E. Di; Hong, Soojie; Charles, Brendan; Lopes, Marilene H.; Beraldo, Flávio H.; Prado, Vânia F.; Prado, Marco A. M.; Duennwald, Martin L.

doi:10.1096/fj.202002645r

Cited by 26 publications

(21 citation statements)

References 78 publications

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“…This apparent discrepancy will have to be resolved methodically in the future. The sensitivity to other types of stresses [125][126][127] may also depend on the exact experimental conditions and on cell type, and will require further investigations.…”

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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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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“…Pharmacological induction of Hsp90 in a SOD1 G93A mouse model shows efficacy in improving motor neuron viability and extending lifespan compared to untreated SOD1 G93A mice [ 15 , 33 ]. One of the proteins that Hsp90 helps to regulate proteostasis of is the trans-active DNA binding protein-43 (TDP-43), a key component of the proteinopathy in most ALS cases [ 67 ]. This is a significant consideration in CNS treatment, as deleting Hsp90 in human neuroblastoma cells leads to a significant increase in phosphorylated TDP-43 aggregates, suggesting the role of Hsp90 in the degradation of the phosphorylated aggregate [ 68 ].…”

Section: Senolytic Agents and Their Limitationsmentioning

confidence: 99%

Senolytics: A Novel Strategy for Neuroprotection in ALS?

Maximova

Werry

Kassiou

2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.

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“…Paradoxically, a genetic screen to identify mediators that regulate mutant Huntington identified knocking down the STI1 homolog in Drosophila reduced the proteotoxicity [216]. In the TDP-43 yeast model for ALS, STI1 deletion resulted in increased TDP-43 toxicity [217]. Interestingly, while moderate overexpression of STI1 protected against TDP-43 toxicity, high levels of STI1 exacerbated it [217].…”

Section: Huntington's Disease and Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Altınok

Sanchez‐Hodge

Stewart

et al. 2021

Cells

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Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

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Hsp90 and its co‐chaperone Sti1 control TDP‐43 misfolding and toxicity

Cited by 26 publications

References 78 publications

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

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

Senolytics: A Novel Strategy for Neuroprotection in ALS?

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

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