Proteasomal surveillance of exposed cysteines
- 1Howard Hughes Medical Institute, Department of Genetics, Harvard University Medical School
Abstract
Cysteine residues are critical for both the catalytic activity and structural stability of many proteins, yet their high chemical reactivity threatens proteome integrity. Whether cells have specialized mechanisms to recognize and eliminate proteins with aberrant or exposed cysteines is unknown. By systematically analyzing the stability of thousands of cysteine-containing peptides, here we identify two complementary surveillance mechanisms targeting proteins with exposed cysteine residues. First, a set of E3 ubiquitin ligases, including AMBRA1, TRPC4AP, FBXO3, and FBXO21, detects double cysteines and targets proteins for ubiquitin-dependent proteasomal degradation. Second, the PSMD14/Rpn11 subunit of the 26S proteasome recognizes exposed cysteines in a ubiquitin-independent manner. Both pathways function in quality control to clear misfolded proteins exposing cysteine residues, including zinc finger-containing proteins. Mutational escape from the ubiquitin-independent pathway through dysregulation of ornithine decarboxylase or FOS levels is responsible for two human diseases, Bachmann-Bupp Syndrome and osteoblastoma, respectively. Our findings reveal conserved mechanisms for degrading proteins with exposed cysteines and uncover an alternative mode of substrate recognition by the 26S proteasome.
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BibTeX
@misc{mena2026proteasomal,
title = {{Proteasomal surveillance of exposed cysteines}},
author = {E. L. Mena and K. C. Dong and A. Kairouz and K. A. Donovan and M. A. Soliman and H.-T. Huang and B. Yildiran and E. S. Fischer and R. I. Sherwood and R. T. Timms and A. Martin and A. Martin and S. J. Elledge},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755535},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755535v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Proteasomal surveillance of exposed cysteines
AU - E. L. Mena
AU - K. C. Dong
AU - A. Kairouz
AU - K. A. Donovan
AU - M. A. Soliman
AU - H.-T. Huang
AU - B. Yildiran
AU - E. S. Fischer
AU - R. I. Sherwood
AU - R. T. Timms
AU - A. Martin
AU - A. Martin
AU - S. J. Elledge
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755535
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755535v1
AB - Cysteine residues are critical for both the catalytic activity and structural stability of many proteins, yet their high chemical reactivity threatens proteome integrity. Whether cells have specialized mechanisms to recognize and eliminate proteins with aberrant or exposed cysteines is unknown. By systematically analyzing the stability of thousands of cysteine-containing peptides, here we identify two complementary surveillance mechanisms targeting proteins with exposed cysteine residues. First, a set of E3 ubiquitin ligases, including AMBRA1, TRPC4AP, FBXO3, and FBXO21, detects double cysteines and targets proteins for ubiquitin-dependent proteasomal degradation. Second, the PSMD14/Rpn11 subunit of the 26S proteasome recognizes exposed cysteines in a ubiquitin-independent manner. Both pathways function in quality control to clear misfolded proteins exposing cysteine residues, including zinc finger-containing proteins. Mutational escape from the ubiquitin-independent pathway through dysregulation of ornithine decarboxylase or FOS levels is responsible for two human diseases, Bachmann-Bupp Syndrome and osteoblastoma, respectively. Our findings reveal conserved mechanisms for degrading proteins with exposed cysteines and uncover an alternative mode of substrate recognition by the 26S proteasome.
ER -