| First Author | Wang Y | Year | 2021 |
| Journal | Immunity | Volume | 54 |
| Issue | 4 | Pages | 632-647.e9 |
| PubMed ID | 33667382 | Mgi Jnum | J:305982 |
| Mgi Id | MGI:6706625 | Doi | 10.1016/j.immuni.2021.02.003 |
| Citation | Wang Y, et al. (2021) Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation. Immunity 54(4):632-647.e9 |
| abstractText | Aging is associated with DNA accumulation and increased homeostatic proliferation of circulating T cells. Although these attributes are associated with aging-related autoimmunity, their direct contributions remain unclear. Conventionally, KU complex, the regulatory subunit of DNA-dependent protein kinase (DNA-PK), together with the catalytic subunit of DNA-PK (DNA-PKcs), mediates DNA damage repair in the nucleus. Here, we found KU complex abundantly expressed in the cytoplasm, where it recognized accumulated cytoplasmic DNA in aged human and mouse CD4(+) T cells. This process enhanced T cell activation and pathology of experimental autoimmune encephalomyelitis (EAE) in aged mice. Mechanistically, KU-mediated DNA sensing facilitated DNA-PKcs recruitment and phosphorylation of the kinase ZAK. This activated AKT and mTOR pathways, promoting CD4(+) T cell proliferation and activation. We developed a specific ZAK inhibitor, which dampened EAE pathology in aged mice. Overall, these findings demonstrate a KU-mediated cytoplasmic DNA-sensing pathway in CD4(+) T cells that potentiates aging-related autoimmunity. |
