Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48.
Overview
- The McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China
- Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
- Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA
- Department of Pathology and Lab Medicine, and Computational Medicine Program, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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/
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Data
Datasets cited
- geo:GSE310700, at NCBI GEO; found in “Data availability”
Data availability
Raw and processed RNA-sequencing data have been deposited in NCBI Gene Expression Omnibus under accession GSE310700 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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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://
BibTeX
@article{altinok2026doma
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/
url = {https://
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/
VL - 302
IS - 10
SP - 113399
SN - 0021-9258
PB - American Society for Biochemistry and Molecular Biology
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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