The molecular chaperone Hsp90α deficiency causes retinal degeneration by disrupting Golgi organization and vesicle transportation in photoreceptors

Abstract Heat shock protein 90 (Hsp90) is an abundant molecular chaperone with two isoforms, Hsp90α and Hsp90β. Hsp90β deficiency causes embryonic lethality, whereas Hsp90α deficiency causes few abnormities except male sterility. In this paper, we reported that Hsp90α was exclusively expressed in the retina, testis, and brain. Its deficiency caused retinitis pigmentosa (RP), a disease leading to blindness. In Hsp90α-deficient mice, the retina was deteriorated and the outer segment of photoreceptor was deformed. Immunofluorescence staining and electron microscopic analysis revealed disintegrated Golgi and aberrant intersegmental vesicle transportation in Hsp90α-deficient photoreceptors. Proteomic analysis identified microtubule-associated protein 1B (MAP1B) as an Hsp90α-associated protein in photoreceptors. Hspα deficiency increased degradation of MAP1B by inducing its ubiquitination, causing α-tubulin deacetylation and microtubule destabilization. Furthermore, the treatment of wild-type mice with 17-DMAG, an Hsp90 inhibitor of geldanamycin derivative, induced the same retinal degeneration as Hsp90α deficiency. Taken together, the microtubule destabilization could be the underlying reason for Hsp90α deficiency-induced RP.

• Publication year

  2019

• Venue

  Journal of Molecular Cell Biology

• Publication date

  2019-08-13

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1093/jmcb/mjz048PMID 31408169PMCID 7181719
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Microtubules acquire resistance from mechanical breakage through intralumenal acetylation

  2017cited by this paper
• Glucocorticoid-Induced Leucine Zipper Protects the Retina From Light-Induced Retinal Degeneration by Inducing Bcl-xL in Rats.

  2017cited by this paper
• Destructive Changes in the Neuronal Structure of the FVB/N Mouse Retina

  2015cited by this paper
• Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs.

  2014cited by this paper
• ISCEV Standard for full-field clinical electroretinography (2015 update)

  2014cited by this paper
• A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors.

  2013cited by this paper
• Genes and mutations causing retinitis pigmentosa

  2013cited by this paper
• Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors.

  2013cited by this paper
• The retinitis pigmentosa 28 protein FAM161A is a novel ciliary protein involved in intermolecular protein interaction and microtubule association.

  2012cited by this paper
• Microtubule stability, Golgi organization, and transport flux require dystonin-a2–MAP1B interaction

  2012cited by this paper
• Spermatogenesis arrest caused by conditional deletion of Hsp90α in adult mice

  2012cited by this paper
• An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST.

  2011cited by this paper
• Electroretinogram in Hereditary Retinal Disorders

  2011cited by this paper
• A Phase I Study of the Heat Shock Protein 90 Inhibitor Alvespimycin (17-DMAG) Given Intravenously to Patients with Advanced Solid Tumors

  2011cited by this paper
• Retinitis Pigmentosa: Genes and Disease Mechanisms

  2011cited by this paper
• Immunocytochemical evidence of Tulp1-dependent outer segment protein transport pathways in photoreceptor cells.

  2011cited by this paper
• Ciliary and Flagellar Membranes

  2011cited by this paper
• The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium.

  2010cited by this paper
• A phase I dose-escalation study of the Hsp90 inhibitor STA-9090 administered twice weekly in patients with solid tumors.

  2010cited by this paper
• The Molecular Chaperone Hsp90α Is Required for Meiotic Progression of Spermatocytes beyond Pachytene in the Mouse

  2010cited by this paper
• Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa.

  2010cited by this paper
• Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.

  2010cited by this paper
• Retinitis pigmentosa and allied conditions today: a paradigm of translational research

  2010cited by this paper
• Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group.

  2010cited by this paper
• Expression of Hsp90 chaperone [corrected] proteins in human tumor tissue.

  2009cited by this paper
• Knockout of GARPs and the β-subunit of the rod cGMP-gated channel disrupts disk morphogenesis and rod outer segment structural integrity

  2009cited by this paper
• Analysis of kinesin-2 function in photoreceptor cells using synchronous Cre-loxP knockout of Kif3a with RHO-Cre.

  2006cited by this paper
• Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines

  2006cited by this paper
• Microtubule-Associated Protein 1B Controls Directionality of Growth Cone Migration and Axonal Branching in Regeneration of Adult Dorsal Root Ganglia Neurons

  2004cited by this paper
• The Retinitis Pigmentosa 1 Protein Is a Photoreceptor Microtubule-Associated Protein

  2004cited by this paper
• The stress response: implications for the clinical development of hsp90 inhibitors.

  2003cited by this paper
• Regulation of Signaling Protein Function and Trafficking by the hsp90/hsp70-Based Chaperone Machinery 1

  2003cited by this paper
• The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance

  2002cited by this paper
• Heat-shock protein 90, a chaperone for folding and regulation

  2002cited by this paper
• VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition.

  2002cited by this paper
• Mutant rab8 Impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods.

  2001cited by this paper
• A simple polymerase chain reaction assay for genotyping the retinal degeneration mutation (Pdebrd1) in FVB/N-derived transgenic mice

  2001cited by this paper
• Assessing retinal function with the multifocal technique.

  2000cited by this paper
• Mice lacking HSP90beta fail to develop a placental labyrinth.

  2000cited by this paper
• Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix.

  1999cited by this paper
• Role of microtubules in the organization of the Golgi complex.

  1999cited by this paper
• Morphological, physiological, and biochemical changes in rhodopsin knockout mice.

  1999cited by this paper
• Mutations in the RP2 gene cause disease in 10% of families with familial X-linked retinitis pigmentosa assessed in this study.

  1999cited by this paper
• Associate Editor: D. Shugar The 90-kDa Molecular Chaperone Family: Structure, Function, and Clinical Applications. A Comprehensive Review

  1998cited by this paper
• Photoreceptor membrane proteins, phototransduction, and retinal degenerative diseases. The Friedenwald Lecture.

  1998cited by this paper
• Overexpression of full- or partial-length MAP4 stabilizes microtubules and alters cell growth.

  1997cited by this paper
• Neuronal abnormalities in microtubule-associated protein 1B mutant mice.

  1996cited by this paper
• [Phase II study].

  1995influential reference
• rab8 in retinal photoreceptors may participate in rhodopsin transport and in rod outer segment disk morphogenesis.

  1995cited by this paper
• Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa.

  1995cited by this paper
• Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci.

  1994cited by this paper
• Microtubule organization and dynamics dependent on microtubule-associated proteins.

  1994cited by this paper
• A role for Hsp90 in cell cycle control: Wee1 tyrosine kinase activity requires interaction with Hsp90.

  1994cited by this paper
• Relationship between the Golgi complex and microtubules enriched in detyrosinated or acetylated α-tubulin: studies on cells recovering from nocodazole and cells in the terminal phase of cytokinesis

  1993cited by this paper
• Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-associated proteins MAP1B, MAP2 or tau.

  1992cited by this paper
• The Photoreceptor Connecting Cilium A Model for the Transition Zone

  1990cited by this paper
• Reduced levels of hsp90 compromise steroid receptor action in vivo

  1990cited by this paper
• Microtubules containing acetylated alpha-tubulin in mammalian cells in culture

  1987cited by this paper
• Eukaryotic Mr 83,000 heat shock protein has a homologue in Escherichia coli.

  1987cited by this paper
• Complete sequence of the heat shock-inducible HSP90 gene of Saccharomyces cerevisiae.

  1984cited by this paper
• Associations of elements of the Golgi apparatus with microtubules

  1984cited by this paper
• Absence of receptor outer segments in the retina of rds mutant mice.

  1981cited by this paper
• KINETICS OF ROD OUTER SEGMENT RENEWAL IN THE DEVELOPING MOUSE RETINA

  1973cited by this paper
• Rhodopsin is the predominant protein of rod outer segment membranes.

  1972cited by this paper
• THE STRUCTURE AND CONCENTRATION OF SOLIDS IN PHOTORECEPTOR CELLS STUDIED BY REFRACTOMETRY AND INTERFERENCE MICROSCOPY

  1957cited by this paper
• Retinitis Pigmentosa

  1941cited by this paper

• Intermediate Filament Protein BFSP1 Maintains Oocyte Asymmetric Division by Modulating Spindle Length

  2025cites this paper
• Mesenchymal Stem Cells With Pharmacological Combinations Necessary to Maximize Retinal Photoreceptor, Outer and Inner Nuclear Layers Rescue

  2025cites this paper
• N-acetyl-l-cysteine ethyl ester (NACET) induces the transcription factor NRF2 and prevents retinal aging and diabetic retinopathy

  2025cites this paper
• TRAP1 and its therapeutic potential.

  2025cites this paper
• AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.

  2025cites this paper
• Recent advances in HSP90 inhibitors as targeted cancer therapy: Chemical scaffolds, isoform selectivity, and clinical progress.

  2025cites this paper
• HSP90α is specifically required for rod photoreceptor function and cannot be replaced by HSP90β

  2025cites this paper
• HSP90 stabilizes visual cycle retinol dehydrogenase 5 in the endoplasmic reticulum by inhibiting its degradation during autophagy

  2024cites this paper
• Extracellular heat shock protein 90 alpha (eHsp90α)'s role in cancer progression and the development of therapeutic strategies.

  2024cites this paper
• Microglia reactivity entails microtubule remodeling from acentrosomal to centrosomal arrays

  2023cites this paper
• Extracellular HSP90 promotes differentiation of lens epithelial cells to fiber cells by activating LRP1‐YAP‐PROX1 axis

  2023cites this paper
• The downregulation of HSP90‐controlled CRALBP expression is associated with age‐related vision attenuation

  2023cites this paper
• Despite their structural similarities, the cytosolic isoforms of human Hsp90 show different behaviour in thermal unfolding due to their conformation: An FTIR study.

  2023cites this paper
• HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits

  2023influential citation
• Elucidation of novel TRAP1-Selective inhibitors that regulate mitochondrial processes.

  2023cites this paper
• CCDC189 affects sperm flagellum formation by interacting with CABCOCO1

  2023cites this paper
• HSP90β prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53

  2023cites this paper
• Distribution of intracellular Ca2+-ATPases in the mouse retina and their involvement in light-induced cone degeneration.

  2023cites this paper
• Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

  2022cites this paper
• Gene expression and functional analysis of Aha1a and Aha1b in stress response in zebrafish.

  2022cites this paper
• HSP90 drives the Rab11a‐mediated vesicular transport of the cell surface receptors in osteoclasts

  2022cites this paper
• Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance

  2022cites this paper
• The biology and inhibition of glucose‐regulated protein 94/gp96

  2022cites this paper
• The Role of Hsp90 in Retinal Proteostasis and Disease

  2022cites this paper
• TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells

  2021cites this paper
• The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with pan-Hsp90 Inhibition.

  2021cites this paper
• Predictive Modeling of MAFLD Based on Hsp90α and the Therapeutic Application of Teprenone in a Diet-Induced Mouse Model

  2021cites this paper
• Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment

  2021cites this paper
• Divergent Effects of HSP70 Overexpression in Photoreceptors During Inherited Retinal Degeneration

  2020cites this paper
• The disruption of protein−protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition

  2020cites this paper
• The molecular chaperone Hsp90 maintains Golgi organization and vesicular trafficking by regulating microtubule stability

  2019cites this paper
• Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases

  2019cites this paper
• Protein Quality Control is a Risk Factor and Therapeutic Target in Toxin-Induced Biliary Atresia

  2019cites this paper