Chaperonin TRiC bridges radial spokes for folding locally translated proteins to sustain mammalian sperm flagellar motility PMID: 41932310

ADC Targets in Oncology

2026-04-10

Chaperonin TRiC bridges radial spokes for folding locally translated proteins to sustain mammalian sperm flagellar motility

Mol Cell. 2026 Apr 2;86(7):1327-1344.e10. doi: 10.1016/j.molcel.2026.03.005.

Xueming Meng ¹ , Luan Li ² , Cheng Lin ¹ , Yun Zhu ³ , Yanyan Feng ⁴ , Qun Zhao ⁵ , Nan Zhao ⁵ , Xuehai Zhou ⁶ , Yujie Tong ¹ , Shanshan Wang ⁷ , Guoliang Yin ³ , Ruimin Liu ¹ , Lihua Zhang ⁸ , Fei Sun ⁹ , Xiumin Yan ¹⁰ , Xueliang Zhu ¹¹ , Yao Cong ¹²

Affiliations

1. Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
2. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
3. State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
4. Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
5. State Key Laboratory of Medical Proteomics, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
6. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
7. The Core Facility Center of CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
8. State Key Laboratory of Medical Proteomics, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: [email protected].
9. State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China. Electronic address: [email protected].
10. Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. Electronic address: [email protected].
11. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
12. Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: [email protected].

Abstract

As Animals evolved from external to internal fertilization, sperm flagella, once transiently propelling sperm in water to reach nearby eggs, developed to beat for days in the viscous female reproductive tract. How flagella are remodeled accordingly remains unclear. Unlike externally fertilizing zebrafish and sea urchins, mammalian flagella feature a barrel between radial spokes (RSs) RS1 and RS2. Here, we show that this RS1-RS2 barrel (RRB) is a unique T-complex protein-1 ring complex (TRiC) that folds locally translated polypeptides to sustain flagellar motility. Cryo-electron microscopy (cryo-EM) reveals a flagellum-specific TRiC structure. An in situ cryo-electron tomography (cryo-ET) map of flagellar axonemes captures the RRB TRiC in an active, substrate-receptive state, with additional densities suggestive of folding substrates and cofactors. Mammalian flagella contain components of translation machineries and locally synthesize proteins. Cross-linking mass spectrometry identifies candidate locally translated axonemal proteins and folding substrates. Furthermore, a TRiC ATPase inhibitor markedly represses mouse sperm motility. Our findings provide insights into flagellar remodeling in internally fertilizing species.

Keywords

TRiC/CCT; axoneme; flagellar TRiC; internal fertilization; local translation; mammalian sperm flagella; protein folding; radial spoke; sperm motility.