PDCD5 promotes substrate release from the TRiC complex in cilia and flagella

Huafang Wei; Qianqian Song; Liying Wang; Qiong Deng; Bingbing Wu; Yinghong Chen; Tingting Han; Yueshuai Guo; Zuyang Li; Fucheng Dong; Shuang Ma; Qiaoyu Zhao; Xiangyi Shi; Chen Pan; Wanying Jiang; Xiaofei Liu; Yingyu Chen; Renjie Jiao; Li Yuan; Chao Liu; Xuejiang Guo; Yao Cong; Wei Li

doi:10.1016/j.molcel.2025.12.012

PDCD5 promotes substrate release from the TRiC complex in cilia and flagella

Mol Cell. 2026 Jan 22;86(2):376-392.e11. doi: 10.1016/j.molcel.2025.12.012. Epub 2026 Jan 7.

Authors

Huafang Wei¹, Qianqian Song², Liying Wang¹, Qiong Deng³, Bingbing Wu¹, Yinghong Chen⁴, Tingting Han¹, Yueshuai Guo⁵, Zuyang Li², Fucheng Dong¹, Shuang Ma¹, Qiaoyu Zhao², Xiangyi Shi⁶, Chen Pan⁷, Wanying Jiang⁸, Xiaofei Liu⁵, Yingyu Chen⁹, Renjie Jiao¹⁰, Li Yuan¹¹, Chao Liu¹², Xuejiang Guo¹³, Yao Cong¹⁴, Wei Li¹⁵

Affiliations

¹ Guangzhou Women and Children's Medical Center, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510623, China.
² 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.
³ Department of Urology, The People's Hospital of Longhua, Shenzhen 518109, China.
⁴ Guangzhou Women and Children's Medical Center, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510623, China; Department of Basic Medical Sciences, Shantou University Medical College, Shantou 515041, China.
⁵ Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China.
⁶ Shanghai Nanoport, Thermo Fisher Scientific, Shanghai 200031, China.
⁷ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China.
⁸ 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.
⁹ Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing 100083, China.
¹⁰ Guangzhou Women and Children's Medical Center, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510623, China. Electronic address: rjiao@gzhmu.edu.cn.
¹¹ Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100020, China. Electronic address: yuanli@ucas.ac.cn.
¹² Guangzhou Women and Children's Medical Center, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510623, China. Electronic address: liuchao@gwcmc.org.
¹³ Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: guo_xuejiang@njmu.edu.cn.
¹⁴ 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: cong@sibcb.ac.cn.
¹⁵ Guangzhou Women and Children's Medical Center, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510623, China. Electronic address: leways@lzu.edu.cn.

PMID: 41506263
DOI: 10.1016/j.molcel.2025.12.012

Abstract

Approximately 10% of eukaryotic proteins are folded by the TRiC/CCT complex (TCP1-ring complex, also called CCT for cytosolic chaperonin containing TCP1), and only open-state TRiC can bind with programmed cell death 5 (PDCD5). However, the physiological role of the PDCD5-TRiC interaction remains elusive. Here, we show that PDCD5 is required for flagellum biogenesis and ciliogenesis and present the PDCD5-TRiC structures in their open states at near-atomic resolution. Mechanically, we find that PDCD5 promotes substrates release by competing with PhLP2A to interact with TRiC, and the depletion of PDCD5 traps flagellum- and cilium-associated proteins within TRiC, finally leading to malformed flagella of spermatids and cilia in mouse ciliated cells. Moreover, we demonstrate that the function of PDCD5 in flagellum biogenesis and ciliogenesis depends on the interaction with TRiC by its C terminus. These findings identify PDCD5 as a TRiC regulator to promote a subset of proteins release.

Keywords: PDCD5; TRiC complex; ciliogenesis; flagellum biogenesis; male infertility; substrate release.

MeSH terms

Animals
Apoptosis Regulatory Proteins* / chemistry
Apoptosis Regulatory Proteins* / genetics
Apoptosis Regulatory Proteins* / metabolism
Chaperonin Containing TCP-1* / chemistry
Chaperonin Containing TCP-1* / genetics
Chaperonin Containing TCP-1* / metabolism
Cilia* / genetics
Cilia* / metabolism
Cilia* / ultrastructure
Flagella* / genetics
Flagella* / metabolism
Flagella* / ultrastructure
HEK293 Cells
Humans
Male
Mice
Neoplasm Proteins* / genetics
Neoplasm Proteins* / metabolism
Protein Binding

Substances

Apoptosis Regulatory Proteins
Chaperonin Containing TCP-1
PDCD5 protein, human
Neoplasm Proteins