Ku limits RNA-induced innate immunity to allow Alu expansion in primates

Yimeng Zhu, Angelina Li, Suvrajit Maji, Brian J. Lee, Sophie M. Korn, Jake A. Gertie, Tyler J. Dorrity, Jianhua Wang, Kyle J. Wang, Amandine Pelletier, Daniel F. Moakley, Rachel D. Kelly, Antony B. Holmes, Raul Rabadan, David R. Edgell, Caroline Schild-Poulter, Mauro Modesti, Anna-Lena Steckelberg, Eric A. Hendrickson, Hachung Chung, Chaolin Zhang () and Shan Zha ()
Additional contact information
Yimeng Zhu: Columbia University
Angelina Li: Columbia University
Suvrajit Maji: Columbia University
Brian J. Lee: Columbia University
Sophie M. Korn: Columbia University
Jake A. Gertie: Columbia University
Tyler J. Dorrity: Columbia University
Jianhua Wang: Columbia University
Kyle J. Wang: Columbia University
Amandine Pelletier: Aix Marseille Univiversité
Daniel F. Moakley: Columbia University
Rachel D. Kelly: Western University
Antony B. Holmes: Columbia University
Raul Rabadan: Columbia University
David R. Edgell: Western University
Caroline Schild-Poulter: Western University
Mauro Modesti: Aix Marseille Univiversité
Anna-Lena Steckelberg: Columbia University
Eric A. Hendrickson: Univeristy of Virginia Medical School
Hachung Chung: Columbia University
Chaolin Zhang: Columbia University
Shan Zha: Columbia University

Nature, 2025, vol. 643, issue 8071, 562-571

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09104-w Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:643:y:2025:i:8071:d:10.1038_s41586-025-09104-w

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09104-w

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().