| RRC ID |
85280
|
| 著者 |
Zhu Y, Li A, Maji S, Lee BJ, Korn SM, Gertie JA, Dorrity TJ, Wang J, Wang KJ, Pelletier A, Moakley DF, Kelly RD, Holmes AB, Rabadan R, Edgell DR, Schild-Poulter C, Modesti M, Steckelberg AL, Hendrickson EA, Chung H, Zhang C, Zha S.
|
| タイトル |
Ku limits RNA-induced innate immunity to allow Alu expansion in primates.
|
| ジャーナル |
Nature
|
| Abstract |
Ku70 and Ku80 form the Ku heterodimer, a ring-shaped complex that initiates the non-homologous end-joining (NHEJ) DNA repair pathway1. Ku binds to double-stranded DNA ends and recruits other NHEJ factors, including LIG4 and DNA-PKcs. Although Ku can bind to double-stranded RNA (dsRNA)2 and trap mutated DNA-PKcs on ribosomal RNA3,4, the physiological role of the Ku-RNA interaction in otherwise wild-type cells remains unclear. Notably, Ku is dispensable for mouse development5,6 but is essential in human cells7. Despite their similar genome sizes, human cells express about 100-fold more Ku than mouse cells, suggesting that Ku has functions beyond NHEJ, possibly through a dose-sensitive interaction with dsRNA, which binds Ku 10 to 100 times more weakly than double-stranded DNA2,8. Here, Ku depletion induces profound interferon and NF-κB signalling via the dsRNA sensor MDA5-RIG-I and MAVS. Prolonged Ku degradation further activates other dsRNA sensors, especially PKR (also known as EIF2AK2) (suppressing translation) and OAS-RNaseL (cleaving ribosomal RNA), leading to growth arrest and cell death. Knockout of MAVS, RIG-I or MDA5 suppressed interferon signalling and, similarly to PKR knockout, partially rescued Ku-depleted human cells. Ku crosslinking and immunoprecipitation analyses revealed binding of Ku to diverse dsRNA molecules, predominantly stem-loops in primate-specific antisense Alu elements9 in introns and 3' untranslated regions. Ku expression is higher in primates than in non-primate mammals and is tightly correlated with Alu expansion. Thus, Ku has a vital role in accommodating Alu expansion in primates, limiting dsRNA-induced innate immunity, which explains its high expression and essential function in human cells.
|
| 巻・号 |
643(8071)
|
| ページ |
562-571
|
| 公開日 |
2025-7-1
|
| DOI |
10.1038/s41586-025-09104-w
|
| PII |
10.1038/s41586-025-09104-w
|
| PMID |
40373806
|
| MeSH |
Alu Elements* / genetics
Animals
DNA End-Joining Repair
Female
Humans
Immunity, Innate* / genetics
Immunity, Innate* / immunology
Interferons / immunology
Interferons / metabolism
Ku Autoantigen* / deficiency
Ku Autoantigen* / genetics
Ku Autoantigen* / metabolism
Male
Mice
NF-kappa B / metabolism
Primates* / genetics
Primates* / immunology
Proto-Oncogene Mas
RNA, Double-Stranded* / immunology
RNA, Double-Stranded* / metabolism
Signal Transduction
|
| IF |
42.779
|
| リソース情報 |
| ヒト・動物細胞 |
HCT116 Tet-OsTIR1(RCB4663) |
