美国哥伦比亚大学Shan Zha团队取得一项新突破。他们的最新研究揭示了Ku限制RNA诱导的先天免疫，使Alu在灵长类动物中扩增。2025年5月15日出版的《自然》发表了这项成果。

有趣的是，Ku对小鼠的发育是必不可少的，但对人类细胞却是必不可少的尽管基因组大小相似，但人类细胞比小鼠细胞多表达约100倍的Ku，这意味着功能超出了NHEJ -可能是通过与dsRNA的剂量敏感相互作用，dsRNA与Ku的结合比dsDNA弱10~100倍。研究Ku在人类细胞中的重要性，该课题组人员发现，与LIG4不同，Ku耗损通过dsRNA传感器MDA5/RIG-I和MAVS诱导深度干扰素（IFN）和NF-kB信号传导。延长的Ku降解进一步激活其他dsRNA传感器，特别是PKR（抑制翻译）和OAS/RNaseL（切割rRNA），导致生长停滞和细胞死亡。MAVS、RIG-1或MDA5敲除抑制IFN信号，并且像PKR敲除一样，都部分地挽救了缺钾的人类细胞。

Ku- irCLIP分析显示Ku与多种dsRNA结合，主要是在内含子和3'-UTRs中灵长类特异性反义Alu元件的茎环上。Ku表达在高等灵长类动物中急剧上升，与Alu扩增密切相关（r = 0.94/0.95）。因此，Ku通过限制dsRNA诱导的先天免疫，在灵长类动物中调节Alu扩增中起着至关重要的作用，这解释了Ku在人类细胞中的高表达及其必要性。

据悉，Ku70和Ku80形成Ku，一个启动非同源末端连接（NHEJ） DNA修复途径的环状复合体Ku结合双链DNA （dsDNA）末端并招募其他NHEJ因子（如LIG4， DNA-PKcs）。虽然Ku可以结合双链RNA (dsRNA)并在核糖体RNA （rRNA）上捕获突变DNA-PKcs，但在其他野生型细胞中Ku-RNA相互作用的生理作用尚不清楚。

附：英文原文

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

Author: Zhu, Yimeng, Li, Angelina, Maji, Suvrajit, Lee, Brian J., Korn, Sophie M., Gertie, Jake A., Dorrity, Tyler J., Wang, Jianhua, Wang, Kyle J., Pelletier, Amandine, Moakley, Daniel F., Kelly, Rachel D., Holmes, Antony B., Rabadan, Raul, Edgell, David R., Poulter, Caroline Schild, Modesti, Mauro, Steckelberg, Anna-Lena, Hendrickson, Eric A., Chung, Hachung, Zhang, Chaolin, Zha, Shan

Issue&Volume: 2025-05-15

Abstract: Ku70 and Ku80 form Ku, a ring-shaped complex that initiates the non-homologous end-joining (NHEJ) DNA repair pathway.1 Ku binds to double-stranded DNA (dsDNA) ends and recruits other NHEJ factors (e.g., LIG4, DNA-PKcs). While Ku can bind to double-stranded RNA (dsRNA)2 and trap mutated-DNA-PKcs on ribosomal RNA (rRNA),3,4 the physiological role on Ku-RNA interaction in otherwise wildtype cells remains unclear. Intriguingly, Ku is dispensable for murine development5,6 but essential in human cells.7 Despite similar genome sizes, human cells express ~100-fold more Ku than mouse cells, implying functions beyond NHEJ - possibly through a dose-sensitive interaction with dsRNA, which binds Ku 10~100 times weaker than dsDNA.2,8 Investigating Ku’s essentiality in human cells, we found that Ku-depletion - unlike LIG4 - induces profound interferon (IFN) and NF-kB signaling via dsRNA-sensor MDA5/RIG-I and MAVS. Prolonged Ku-degradation further activates other dsRNA sensors, especially PKR (suppressing translation) and OAS/RNaseL (cleaving rRNA), leading to growth arrest and cell death. MAVS, RIG-I, or MDA5 knockouts suppressed IFN signaling and, like PKR knockouts, all partially rescued Ku-depleted human cells. Ku-irCLIP analyses revealed Ku binding to diverse dsRNA, predominantly stem-loops in primate-specific antisense Alu elements9 in introns and 3’-UTRs. Ku expression rose sharply in higher primates, correlating tightly with Alu-expansion (r = 0.94/0.95). Thus, Ku plays a vital role in accommodating Alu-expansion in primates by limiting dsRNA-induced innate immunity, explaining both Ku’s elevated expression and its essentiality in human cells.

DOI: 10.1038/s41586-025-09104-w

Source: https://www.nature.com/articles/s41586-025-09104-w