DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis

Lan Shao, Jörg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)415-427
Number of pages13
JournalEMBO Molecular Medicine
Volume2
Issue number10
DOIs
StatePublished - Oct 2010

Keywords

  • Apoptosis
  • DNA damage
  • DNA-PKcs
  • Rheumatoid arthritis
  • T-cell

ASJC Scopus subject areas

  • Molecular Medicine

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