DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis.
Open accessAbstract
In the autoimmune syndrome rheumatoid arthritis (RA), T cells and T-cell precursors have age-inappropriate shortening of telomeres and accumulate deoxyribonucleic acid (DNA) double strand breaks. Whether damaged DNA elicits DNA repair activity and how this affects T-cell function and survival is unknown. Here, we report that naïve and resting T cells from RA patients are susceptible to undergo apoptosis. In such T cells, unrepaired DNA stimulates a p53-ataxia telangiectasia mutated-independent pathway involving the non-homologous-end-joining protein DNA-protein kinase catalytic subunit (DNA-PKcs). Upregulation of DNA-PKcs transcription, protein expression and phosphorylation in RA T cells co-occurs with diminished expression of the Ku70/80 heterodimer, limiting DNA repair capacity. Inhibition of DNA-PKcs kinase activity or gene silencing of DNA-PKcs protects RA T cells from apoptosis. DNA-PKcs induces T-cell death by activating the JNK pathway and upregulating the apoptogenic BH3-only proteins Bim and Bmf. In essence, in RA, the DNA-PKcs-JNK-Bim/Bmf axis transmits genotoxic stress into shortened survival of naïve resting T cells, imposing chronic proliferative turnover of the immune system and premature immunosenescence. Therapeutic blockade of the DNA-PK-dependent cell-death machinery may rejuvenate the immune system in RA.
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HIV-associated inflammation and/or exposure to nucleoside analogues have been associated with changes in telomere-related and other key biologic pathways.
“HIV-associated inflammation and/or exposure to nucleoside analogues have been associated with changes in these and other key biologic pathways (33–40).”
From HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group (2012) · cites this paper as [33]
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- Authors
- Shao, L., Goronzy, J. J., & Weyand, C. M.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Weyand, Cornelia M.
- Venue
- EMBO Molecular Medicine
- Published
- 2010-09-28
- Volume
- 2
- Issue
- 10
- Pages
- 415-427
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3017722
- OpenAlex
- W2149954943
- Cited by
- 69
- References
- 64
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 10 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 2 · 2014: 3 · 2013: 7 · 2012: 6
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI044142, U19-AI57266, R01AI44142, U19AI057266)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR042527, R01AR42527)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- rheumatoid arthritis, DNA-PKcs, T cell apoptosis, DNA double-strand breaks, telomere shortening, Ku70/80 heterodimer, non-homologous end joining, JNK signaling, building information modeling, BMF, BH3-only proteins, immunosenescence, T cell precursors, DNA repair, autoimmune disease
- MeSH terms
- Bcl-2-Like Protein 11, Aged, Arthritis, Rheumatoid, DNA Repair, Female, Humans, Immune Tolerance, Male, Membrane Proteins, Middle Aged, Proto-Oncogene Proteins, T-Lymphocytes, Signal Transduction, Apoptosis, Catalytic Domain, Gene Silencing, MAP Kinase Kinase 4, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, DNA-Activated Protein Kinase
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