The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes

• 成果类型: Article
• 署名作者: Liao, Meimei; Liu, Yanqin; Xu, Zhancong; Fang, Mingxu; Yu, Ziqing; Cui, Yufan; Sun, Zhengda; Huo, Ran; Yang, Jieyu; Huang, Fusheng; Liu, Mingming; Zhou, Qin; Song, Xiaocui; Han, Hui; Chen, She; Xu, Xiaodong; Qin, Ximing; He, Qun; Ju, Dapeng; Wang, Tao; Thakkar, Nirav; Hardin, Paul E.; Golden, Susan S.; Zhang, Eric Erquan
• 署名单位: National Institute of Biological Sciences, Beijing; Tsinghua University; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; University of California System; University of California San Diego; Tsinghua University; China Agricultural University; Henan University; Anhui University; Chongqing Medical University; Texas A&M University System; Texas A&M University College Station; Texas A&M University System; Texas A&M University College Station; University of California System; University of California San Diego
• 刊物名称: Nature
• ISSN/ISSBN: 0028-0889
• DOI: 10.1038/s41586-025-08797-3
• 发表日期: 2025-06-05
• 关键词: drosophila circadian clock; codon usage affects; gene; constraints; expression; EVOLUTION; feedback; platform; network; atpase

摘要

The eukaryotic circadian clock keeps time by using a transcription-translation feedback loop, which exhibits an architecture that is conserved across a diverse range of organisms, including fungi, plants and animals1. Despite their mechanistic similarity, the molecular components of these clocks indicate a lack of common ancestry2. Our study reveals that RUVBL2, which is a P-loop NTPase enzyme previously shown to affect circadian phase and amplitude as part of mammalian clock super-complexes, influences the circadian period through its remarkably slow ATPase activity, resembling the well-characterized KaiC-based clock in cyanobacteria. A screen of RUVBL2 variants identified arrhythmic, short-period and long-period mutants that altered circadian locomotor activity rhythms following delivery by adeno-associated virus to the murine suprachiasmatic nucleus. Enzymatic assays showed that wild-type RUVBL2 hydrolyses only around 13 ATP molecules a day, a vastly reduced turnover compared with typical ATPases. Notably, physical interactions between RUVBL2 orthologues and core clock proteins in humans, Drosophila and the fungus Neurospora, along with consistent circadian phenotypes of RUVBL2-mutant orthologues across species, reinforce their clock-related function in eukaryotes. Thus, as well as establishing RUVBL2 as a common core component in eukaryotic clocks, our study supports the idea that slow ATPase activity, initially discovered in cyanobacteria, is a shared feature of eukaryotic clocks.