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Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48.

Overview

Authors: Selin Altinok1,2, Ethan Paulakonis2, Michael F Almeida1, Isaac Hwang1, Rebekah Sanchez-Hodge1, Christina D’Ovidio1, Alison S Eidman2, Shreesti Shrestha3, Georgia Roper1, Grant Irons1, Elena Vargas1, Ivy Peng1, Morcos Saeed1, Aliyaa Pathan1, Mel N Azin1, Joseph Latham1, Sarah M Ronnebaum1, Chang-he Shi4, Mark J Ranek5, K Matthew Scaglione6, Richard C Page3, Nicholas G Brown2, Jonathan C Schisler1,2,7
ORCID iDs: Selin Altinok, Ethan Paulakonis, Michael F Almeida, Isaac Hwang, Rebekah Sanchez-Hodge, Shreesti Shrestha, Georgia Roper, Morcos Saeed, Mel N Azin, Joseph Latham, Sarah M Ronnebaum, Mark J Ranek, K Matthew Scaglione, Richard C Page, Nicholas G Brown, Jonathan C Schisler
  1. The McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  2. Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  3. Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA
  4. Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China
  5. Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  6. Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA
  7. Department of Pathology and Lab Medicine, and Computational Medicine Program, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Institutions: University of North Carolina at Chapel Hill (United States); Miami University (United States); Zhengzhou University (China); Johns Hopkins Medicine (United States); Johns Hopkins Hospital (United States); Duke University (United States)
Journal: The Journal of biological chemistry, volume 302, issue 10, article 113399
Dates: received 12 January 2026; published online 7 August 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.jbc.2026.113399 · PMID 42567515 · PMCID PMC13570301 · OpenAlex W7201869446
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), other condition (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: CHIP, co-chaperone, E3 ubiquitin ligase, genotype-phenotype correlation, heat shock response, HSF1, HSP70, STUB1, molecular chaperone, oligomerization, protein quality control, spinocerebellar ataxia type 48
Topic: Genetic Neurodegenerative Diseases (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: National Cancer Institute (P30CA016086); NIGMS NIH HHS (R35 GM128595, R01 GM061728); NCI NIH HHS (P30 CA016086); NIA NIH HHS (R01 AG061188, R01 AG066710); American Heart Association Inc; National Institute on Aging; NHLBI NIH HHS (T32 HL069768); NICHD NIH HHS (P50 HD103573); BrightFocus Foundation; National Heart, Lung, and Blood Institute; National Ataxia Foundation
Citations: not cited yet (Europe PMC); 81 references in the paper
Research resources: RRID:SCR_019060

Abstract

The carboxyl terminus of Hsp70-interacting protein (CHIP, encoded by STUB1) combines co-chaperone and E3 ubiquitin ligase activities to regulate protein quality control. Heterozygous mutations in STUB1 cause spinocerebellar ataxia type 48 (SCA48), a progressive cerebellar ataxia with variable extrapyramidal and cognitive features. To understand the molecular basis of this variability, we systematically analyzed 13 SCA48-associated variants spanning the TPR and U-box domains through recombinant protein biochemistry and cellular models. TPR variants retained intrinsic ligase activity but showed significantly reduced HSP70 binding, impaired substrate ubiquitination, and decreased stability. Conversely, U-box variants abolished ligase function, promoted the formation of high-molecular-weight oligomers, and often increased CHIP levels while only partially impairing co-chaperone activity. Many mutants displayed temperature-sensitive defects and defective stress-induced nuclear translocation. Principal component analysis revealed distinct biochemical clustering specific to each domain. RNA-seq following STUB1 knockdown modeled CHIP insufficiency and showed preserved HSF1-dependent transactivation, but loss of CHIP’s capacity to amplify ubiquitination, chaperone function, and stress-related transcriptional programs. Meta-analysis of 87 SCA48 patients linked TPR-like biochemical signatures to upper motor neuron involvement and U-box-like profiles to prominent dysarthria. Overall, these data indicate that SCA48 results from domain-specific disruption of CHIP’s dual functions, producing varying degrees of CHIP insufficiency and/or gain-of-toxic effects that together contribute to the phenotypic diversity observed across patients. This work refines the mechanistic framework for SCA48 pathogenesis and highlights strategies for therapeutic modulation of residual CHIP activity.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

Data availability

Raw and processed RNA-sequencing data have been deposited in NCBI Gene Expression Omnibus under accession GSE310700 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE310700) and are publicly available. All other data supporting the findings of this study are available within the article and its supplementary information files, or from the corresponding authors upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 3, 28 September 2026

  • Authors: added Ethan Paulakonis (0009-0003-0494-8384); Georgia Roper (0009-0007-0716-4672); Morcos Saeed (0009-0000-6696-0926); Mel N Azin (0009-0006-9286-9337); Joseph Latham (0009-0002-3094-5104); Sarah M Ronnebaum (0000-0003-4787-754X); Mark J Ranek (0000-0002-4970-8988); K Matthew Scaglione (0000-0002-3858-9418); Richard C Page (0000-0002-3006-3171); Jonathan C Schisler (0000-0001-7382-2783); removed Ethan Paulakonis; Georgia Roper; Morcos Saeed; Mel N Azin; Joseph Latham; Sarah M Ronnebaum; Mark J Ranek; K Matthew Scaglione; Richard C Page; Jonathan C Schisler

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 23 authors, 12 keywords, 11 funders, 81 references, 1 RRID.

Cite

This paper

Altinok, S., Paulakonis, E., Almeida, M. F., Hwang, I., Sanchez-Hodge, R., D’Ovidio, C., Eidman, A. S., Shrestha, S., Roper, G., Irons, G., Vargas, E., Peng, I., Saeed, M., Pathan, A., Azin, M. N., Latham, J., Ronnebaum, S. M., Shi, C.-h., Ranek, M. J., . . . Schisler, J. C. (2026). Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48. The Journal of biological chemistry, 302(10), 113399. https://doi.org/10.1016/j.jbc.2026.113399

BibTeX

@article{altinok2026domain,
author = {Altinok, Selin and Paulakonis, Ethan and Almeida, Michael F and Hwang, Isaac and Sanchez-Hodge, Rebekah and D’Ovidio, Christina and Eidman, Alison S and Shrestha, Shreesti and Roper, Georgia and Irons, Grant and Vargas, Elena and Peng, Ivy and Saeed, Morcos and Pathan, Aliyaa and Azin, Mel N and Latham, Joseph and Ronnebaum, Sarah M and Shi, Chang-he and Ranek, Mark J and Scaglione, K Matthew and Page, Richard C and Brown, Nicholas G and Schisler, Jonathan C},
title = {{Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48}},
journal = {The Journal of biological chemistry},
year = {2026},
month = aug,
volume = {302},
number = {10},
pages = {113399},
publisher = {American Society for Biochemistry and Molecular Biology},
issn = {0021-9258},
doi = {10.1016/j.jbc.2026.113399},
url = {https://doi.org/10.1016/j.jbc.2026.113399},
pmid = {42567515},
pmcid = {PMC13570301}
}

RIS

TY - JOUR
AU - Altinok, Selin
AU - Paulakonis, Ethan
AU - Almeida, Michael F
AU - Hwang, Isaac
AU - Sanchez-Hodge, Rebekah
AU - D’Ovidio, Christina
AU - Eidman, Alison S
AU - Shrestha, Shreesti
AU - Roper, Georgia
AU - Irons, Grant
AU - Vargas, Elena
AU - Peng, Ivy
AU - Saeed, Morcos
AU - Pathan, Aliyaa
AU - Azin, Mel N
AU - Latham, Joseph
AU - Ronnebaum, Sarah M
AU - Shi, Chang-he
AU - Ranek, Mark J
AU - Scaglione, K Matthew
AU - Page, Richard C
AU - Brown, Nicholas G
AU - Schisler, Jonathan C
TI - Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48
T2 - The Journal of biological chemistry
J2 - J Biol Chem
PY - 2026
DA - 2026/08/07
VL - 302
IS - 10
SP - 113399
SN - 0021-9258
PB - American Society for Biochemistry and Molecular Biology
DO - 10.1016/j.jbc.2026.113399
UR - https://doi.org/10.1016/j.jbc.2026.113399
LA - en
ER -

CSL-JSON

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