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

Altınok, Selin; Sanchez‐Hodge, Rebekah; Stewart, Mariah; Smith, Kaitlan; Schisler, Jonathan C.

doi:10.3390/cells10113121

Cited by 14 publications

(5 citation statements)

References 325 publications

(444 reference statements)

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“…The various Hsps work in close association with their respective co-chaperones (Altinok et al, 2021; Joshi et al, 2018). Expression patterns of the diverse co-chaperones and their roles in survival and progression of the tumorous clones remain to be examined.…”

Section: Discussionmentioning

confidence: 99%

Elevation of major constitutive heat shock proteins is heat shock factor independent and essential for establishment and growth of Lgl loss and Yorkie gain mediated tumors in Drosophila

Singh

Lakhotia

2021

Preprint

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Cancer cells experience a variety of stresses like hypoxia, lack of nutrients, DNA damage and immune responses, which trigger several processes to drive genomic instability and mutation, alterations in gene expression programs, and reprogramming of the metabolic pathways to escape growth inhibition signaling, and acquire resistance to the immune surveillance. Different heat shock proteins are expressed at elevated levels in cancer cells. However, their specific roles in initiation, establishment and progression of cancers are still not clear. Here using the loss of function allele of the apico-basal polarity gene, lgl, we have established models for induction of tumorous somatic clones of different genetic constitutions at defined developmental times for examination of temporal and spatial patterns of expression of the major heat shock protein families, namely Hsp83, Hsp70, Hsp60 and Hsp27. The Hsp83, Hsp60 and Hsp27 begin to express in all cells of the tumor at high levels since early stages (48hr after tumor induction) and continue their high expression at later stages when the tumorous clones accumulate F-actin and get transformed. Levels of the heat shock cognate Hsc70 proteins also follow the same pattern as the other Hsps. However, the major stress-inducible Hsp70 is not expressed at early stages of tumor growth, but expresses at a later stage only in a few cells in a given lgl loss of function clone, which also shows high F-actin aggregates. Thus, the major Hsps, except the Hsp70, seems to be involved in early as well as late stages of epithelial tumors induced by loss of the Lgl cell polarity protein, while the Hsp70 expression in a few cells coincides with their getting transformed. This model will be useful for further genetic studies to dissect specific roles of different Hsps in tumor development and their therapeutic manipulation.

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Section: Discussionmentioning

confidence: 99%

Elevation of major constitutive heat shock proteins is heat shock factor independent and essential for establishment and growth of Lgl loss and Yorkie gain mediated tumors in Drosophila

Singh

Lakhotia

2021

Preprint

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“…These molecules are required in higher eukaryotes, to aid chaperones. They are responsible for client protein presentation and regulating their respective chaperone activity as well as ATPse activity [33,34]. Hsp90 cochaperones are structurally distinct, and their interaction may depend on cofactors of stoichiometry [33][34][35] as in the following examples: Hop; Ahas; p23; and SGT.…”

Section: Hsp90 Cochaperonesmentioning

confidence: 99%

New Insights into Hsp90 Structural Plasticity Revealed by cryoEM

Minari,

Balasco Serrão,

Borges

2024

BioChem

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Heat Shock Protein 90 (Hsp90) acts as a crucial molecular chaperone, playing an essential role in activating numerous signaling proteins. The intricate mechanism of Hsp90 involving ATPase-coupled conformational changes and interactions with cochaperone proteins has been elucidated through biochemical and structural analyses, revealing its activation mechanism and its diverse set of “client” proteins. Despite recent advancements, certain aspects of Hsp90’s ATPase-coupled mechanism remain contentious, and the specific nature of the alterations induced by Hsp90 in client proteins remains largely undiscovered. In this review, we explore the current understanding of Hsp90’s structure and function, drawing insights from single-particle cryoEM studies. Structural studies on Hsp90 using cryoEM have provided valuable insights into the structural dynamics and interactions of this molecular chaperone. CryoEM structures have been instrumental in understanding the ATPase-coupled conformational changes that Hsp90 undergoes during its chaperone cycle. We also highlight recent progress in elucidating the structure of the ATP-bound state of the complete dimeric chaperone. Furthermore, we delve into the roles played by the multitude of cochaperones that collaborate with Hsp90, providing a glimpse into their biochemical mechanisms through the newly obtained cryoEM structures of Hsp90 cochaperone complexes.

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“…The investigation of HSPs as modulators of the immune response to foreign antigens may strengthen the candidacy of molecular mimicry as a causative factor in autoimmune hepatitis. It may also suggest HSP-directed therapeutic strategies for future study [ 254 , 258 – 260 ].…”

Section: Prospect Of Molecular Mimicry As a Cause Of Autoimmune Hepat...mentioning

confidence: 99%

Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis

Czaja

2023

Dig Dis Sci

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Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.

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

Cited by 14 publications

References 325 publications

Elevation of major constitutive heat shock proteins is heat shock factor independent and essential for establishment and growth of Lgl loss and Yorkie gain mediated tumors in Drosophila

Elevation of major constitutive heat shock proteins is heat shock factor independent and essential for establishment and growth of Lgl loss and Yorkie gain mediated tumors in Drosophila

New Insights into Hsp90 Structural Plasticity Revealed by cryoEM

Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis

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