Evidence map›Paper›PMID 42856651›Full record

ArticlebioRxiv : the preprint server for biology2026

Proteasomal surveillance of exposed cysteines.

Elijah L Mena, Ken C Dong, Anthony Kairouz, Katherine A Donovan, Mostafa A Soliman, Hai-Tsang Huang, Bercin Yildiran, Eric S Fischer, Richard I Sherwood, Richard T Timms and 2 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Elijah L MenaDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-9980-9018
Ken C DongDepartment of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
Anthony KairouzDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
Katherine A DonovanDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Mostafa A SolimanDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
Hai-Tsang HuangBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Bercin YildiranBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Eric S FischerDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Richard I SherwoodDivision of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Richard T TimmsCambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, UK.
Andreas MartinDepartment of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
Stephen J ElledgeDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-7923-6283

Funding

Ubiquitin Mediated Proteolysis and Cell Cycle ControlR01AG011085 · NIA · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JEFFREY W HARPER · 1993 to 2026
$10.9M
Characterization of a ubiquitin-independent pathway for proteasomal degradationK99AG081456 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI MENA, ELIJAH L · 2023 to 2024
$273k
NIA NIH HHS K99 AG081456NIA NIH HHS R01 AG011085Wellcome Trust
6 · The paper itself

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.

Indexed as

26S proteasomecysteineFOSornithine decarboxylase (ODC)proteostasisubiquitin-independent degradationUPSzinc

Identifiers

PMID42856651
PMCPMC13648738

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.