Mechanism of orphan subunit recognition during assembly quality control
Open accessAbstract
Cells contain numerous abundant molecular machines assembled from multiple subunits. Imbalances in subunit production and failed assembly generate orphan subunits that are eliminated by poorly defined pathways. Here, we determined how orphan subunits of the cytosolic chaperonin CCT are recognized. Several unassembled CCT subunits recruited the E3 ubiquitin ligase HERC2 using ZNRD2 as an adaptor. Both factors were necessary for orphan CCT subunit degradation in cells, sufficient for CCT subunit ubiquitination with purified factors, and necessary for optimal cell fitness. Domain mapping and structure prediction defined the molecular features of a minimal HERC2-ZNRD2-CCT module. The structural model, whose key elements were validated in cells using point mutants, shows why ZNRD2 selectively recognizes multiple orphaned CCT subunits without engaging assembled CCT. Our findings reveal how failures during CCT assembly are monitored and provide a paradigm for the molecular recognition of orphan subunits, the largest source of quality control substrates in cells.
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The reduction of Exo9 and EXOSC10 protein abundance across all subunits is caused by orphan protein decay because of the increased production of the unstable, and likely unusable, short EXOSC3 proteoform.
“We conclude that the reduction of Exo9 and EXOSC10 protein abundance across all subunits is caused by orphan protein decay because of the increased production of the unstable, and likely unusable, short EXOSC3 proteoform107–109.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [109]
The Introduction states that eliminating one complex subunit usually destabilizes its partners and describes degradation of unassembled subunits. This supports orphan-protein decay as a general mechanism, but the paper does not establish that a short EXOSC3 proteoform causes reduced Exo9 and EXOSC10 abundance; that specific conclusion is the citing authors’ own. (LLM, conf=0.84)
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Yang, S., Ting, C.-Y., & Lilly, M. (2024) · Molecules and Cells · doi:10.1016/j.molcel.2024.01.012 · Cited by 6 · see citing works
TanGIBLE: A selective probe for evaluating hydrophobicity-exposed defective proteins in live cells
Iwasa, Y., Miyata, S., Tomita, T., Yokota, N., Miyauchi, M., Mori, R., Matsushita, S., Suzuki, R., Saeki, Y., & Kawahara, H. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202109010 · Cited by 5 · see citing works
Topology surveillance of the lanosterol demethylase CYP51A1 by signal peptide peptidase
Sergejevs, N., Avci, D., van de Weijer, M. L., Corey, R. A., Lemberg, M. K., & Carvalho, P. (2024) · Journal of Cell Science · doi:10.1242/jcs.262333 · Cited by 5 · see citing works
Shen, F., Liu, Y., Ruan, X., Yan, G., Zhang, L., Fang, J., Lu, H., Hu, Z., & Zhou, X. (2026) · Analytical Chemistry · doi:10.1021/acs.analchem.5c07096 · Cited by 5 · see citing works
Flagg, M. P., Lam, B., Lam, D. K., Le, T. M., Kao, A., Slaiwa, Y. I., & Hampton, R. Y. (2023) · Molecular Biology of the Cell · doi:10.1091/mbc.e23-06-0248 · Cited by 4 · see citing works
Tsopoulidis, N., Yagi, M., Brumbaugh, J., Ito, S., López-Soriano, V., Morris, R., Yoon, Y., Messemer, K. A., Lin, K., Zaniewski, E. F., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68630-x · Cited by 3 · see citing works
Preserve or destroy: Orphan protein proteostasis and the heat shock response
Ali, A., Paracha, S., & Pincus, D. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202407123 · Cited by 4 · see citing works
HERC3 E3 ligase provides an ERAD branch eliminating select membrane proteinsPreprint
Kamada, Y., Ohnishi, Y., Nakashima, C., Fujii, A., Terakawa, M., Hamano, I., Nakayamada, U., Katoh, S., Hirata, N., Tateishi, H., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.16.562477 · Cited by 2 · see citing works
Bhardwaj, V., Swanson, S. K., Florens, L. A., Washburn, M. P., Workman, J. L., & Natarajan, K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.23.660276 · Cited by 2 · see citing works
EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery
Wijeratne, H. R. S., Runnebohm, A. M., Barron, M. P., Hampton, A. J., Li, R., Peck Justice, S. A., Lenceski, S. H., Rooney, J. D., Smith-Kinnaman, W. R., Chang, G. S., et al. (2026) · doi:10.64898/2026.01.26.701775 · Cited by 1 · see citing works
A diverse interactome of the molecular chaperone CCT/TRiC monomers
Córdoba-Beldad, C. M., & Grantham, J. (2025) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2025.151506 · Cited by 1 · see citing works
Targeted Protein Degradation in Escherichia coli - depletion of the essential GroEL using CLIPPERsPreprint
Izert, M. A., Klimecka, M. M., Antosiewicz, A., Wróblewski, K., Kowalski, J. J., Bandyra, K. J., Goral, T., Kmiecik, S., Serwa, R. A., & Górna, M. W. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.29.582761 · Cited by 1 · see citing works
Hsieh, H.-H., & Martin, A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.01.729410 · Cited by 1 · see citing works
Münch, C., & Kirstein, J. (2023) · Cell Stress and Chaperones · doi:10.1007/s12192-023-01383-4
Huang, Y.-Y., Chang, Y.-L., Chen, Y., Chiang, W.-Y., Chiang, A.-T., Hsu, P., & Teng, S. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110914
ZNRD2 Mediated Nucleoprotein Aggregation Impairs Respiratory Syncytial Virus Replication
Zhou, H., He, M., Du, J., Liu, C., Wang, W., Han, Y., Li, Z., Qin, Y., & Chen, M. (2026) · Advanced Science · doi:10.1002/advs.202508811
Bhardwaj, V., Swanson, S. K., Florens, L. A., Washburn, M. P., Workman, J. L., & Natarajan, K. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.111239
Cotranslational Assembly of Oligomeric Proteins
Santos, J., Tans, S. J., Ban, N., Kramer, G., & Bukau, B. (2026) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-051024-124747 · Cited by 2 · see citing works
Sala-Gaston, J., Costa‑Sastre, L., Garcia‑Diez, M., López-Hernández, T., Ramírez, J., Osinalde, N., Valer, J. A., Arnedo-Pac, C., Crosas, B., Baple, E. L., et al. (2026) · Cell Death Discovery · doi:10.1038/s41420-026-03095-x
MSTO1 functions as a TRiC assembly factor linking cytosolic proteostasis to mitochondrial functionPreprint
Bounds, A. M., Higuchi, C., & Hoppins, S. C. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.07.21.739937
BAG6-RNF115 Couples Protein Quality Control with Ribosome AssemblyPreprint
Raiff, A., Zenge, C., Ordureau, A., & Koren, I. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.06.742952
Grantham, J. (2026) · Cell stress & chaperones (Print) · doi:10.1016/j.cstres.2026.100207
- Authors
- Yagita, Y., Zavodszky, E., Peak-Chew, S.-Y., & Hegde, R. S.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Hegde, Ramanujan S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2023-08
- Volume
- 186
- Issue
- 16
- Pages
- 3443-3459.e24
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC10501995
- OpenAlex
- W4385077788
- Cited by
- 30
- References
- 80
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 5 · 2023: 5
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medical Research Council (MC_UP_A022_1007)
- Naito Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- chaperonin CCT, assembly quality control, HERC2, E3 ubiquitin ligase, ubiquitination, protein degradation, molecular recognition, protein complex formation
- MeSH terms
- Humans, Ubiquitin-Protein Ligases, Chaperonin Containing TCP-1
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