Evidence map›Paper›PMID 42906538›Full record

ArticleCell2026

Proteomic atlas of T cell exhaustion defines proteostatic collapse.

Sydnye L Shuttleworth, Michael A Bauer, Dennis W Province, Jessica L Kelliher, Nicole E Scharping, Alexander Monell, Lora J Rogers, Thomas A Williams, Grant T Dawson, Katherine F Wallis and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 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

22 authors.

Sydnye L ShuttleworthDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Michael A BauerDepartment of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Dennis W ProvinceDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Jessica L KelliherDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Nicole E ScharpingSchool of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Alexander MonellSchool of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Lora J RogersDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Thomas A WilliamsDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Grant T DawsonDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Katherine F WallisDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Duah AlkamDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Jacob L EdmondsonDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Daniel FilDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Aaron J StoreyArkana Laboratories, Little Rock, AR 72211, USA.
Anna L BoldingDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Rick D EdmondsonDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Stephanie D ByrumCenter for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Karen E BeenkenDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Samuel G MackintoshDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Ananda W GoldrathSchool of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Alan J TackettDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Brian KossDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: bskoss@uams.edu.

Funding

Discovering T cell proteome turnover dynamics to overcome the solid tumor microenvironmentDP5OD031863 · OD · UNIV OF ARKANSAS FOR MED SCIS · PI KOSS, BRIAN · 2021 to 2025
$1.9M
Targeting the E3 Ligase RNF166 to Prevent T-cell Exhaustion in Solid TumorsR01CA315781 · NCI · UNIV OF ARKANSAS FOR MED SCIS · PI Brian Koss · 2026 to 2026
$592k
NCI NIH HHS R01 CA315781NIH HHS DP5 OD031863
6 · The paper itself

Abstract

T cell exhaustion limits the success of cancer immunotherapies, yet the proteomic changes underlying this dysfunctional state remain poorly understood. We integrated transcriptomics, quantitative proteomics, turnover proteomics, and ubiquitin proteomics to construct a multi-omic atlas of T cell exhaustion. These studies identified pathways regulated through transcriptional and post-translational mechanisms, including degradative and nondegradative ubiquitin modifications, and uncovered widespread changes in proteostasis, metabolism, and DNA repair. Major shifts were revealed in the ubiquitin-proteasome system, as differential expression of E3 ubiquitin ligases correlates with immunotherapy outcomes. These findings position the collapse of proteostasis as a central, underappreciated feature of T cell exhaustion and reveal opportunities to restore T cell function. We demonstrate that overexpression of the E3 ligase RNF166 enhances T cell persistence in vitro and in vivo. This work defines proteome-turnover dynamics as a critical regulatory layer in progressive T cell dysfunction, with broad implications for advancing cancer immunotherapy through manipulation of E3 ligases.

Indexed as

cancer immunotherapyCAR-Tcell therapyE3 ubiquitin ligaseexhaustionhalf-lifeprotein-turnover dynamicsproteostasisT cellubiquitin

Identifiers

PMID42906538
PMCPMC13693510

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.