A germline-specific vesicular structure licenses mRNA activation during spermiogenesis and is hijacked in gastric cancer

  • Sci Bull (Beijing). 2026 May 30;71(10):2574-2590. doi: 10.1016/j.scib.2026.02.056.
Mingxi Liu  1 ,  Zerui Wang  2 ,  Yinuo Li  3 ,  Qingsong Xie  4 ,  Zhuang Xiao  3 ,  Xuezhi He  5 ,  Guanxiong Wang  6 ,  Yang Gao  7 ,  Yini Zhang  7 ,  Lin Zheng  7 ,  Xun Xia  4 ,  Lujie Chen  3 ,  Yue Dong  3 ,  Siyu Liu  3 ,  Xin Zhang  3 ,  Chuan Xu  8 ,  Shuhui Bian  3 ,  Yan Yuan  3 ,  Huan Wu  9 ,  Yunxia Cao  10 ,  Jintao Zhang  11 ,  Rong Hua  12 ,  Xiaojin He  13
Affiliations
  • 1. State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
  • 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Changzhou 213000, China.
  • 3. State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 4. Department of Obstetrics and Gynecology, and NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
  • 5. Department of Human Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing 211166, China.
  • 6. Department of Obstetrics and Gynecology, and NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 7. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 8. Department of Obstetrics and Gynecology, and NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China.
  • 9. Department of Obstetrics and Gynecology, and NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Disorders and Obstetrics and Gynaecology Diseases, Hefei 230032, China.
  • 10. Department of Obstetrics and Gynecology, and NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Anhui Medical University, Hefei 230032, China; Anhui Province Key Laboratory of Reproductive Disorders and Obstetrics and Gynaecology Diseases, Hefei 230032, China. Electronic address: [email protected].
  • 11. State Key Laboratory of Reproductive Medicine and Offspring Health, Clinical Center of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: [email protected].
  • 12. Department of Obstetrics and Gynecology, and NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Anhui Medical University, Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China. Electronic address: [email protected].
  • 13. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. Electronic address: [email protected].
PMID: 41925442 DOI: 10.1016/j.scib.2026.02.056
Abstract

Post-transcriptional regulation is pivotal for cellular differentiation, yet how translationally silent mRNAs are selectively reactivated remains elusive. Here, we identify the MEX3D-HIP1 (MX-H) pathway and its associated organelle, the MEX3D-associated lysosomal vesicle (MXLV), as a shared system governing mRNA activation during spermiogenesis. Our data support a model in which MEX3D acts as an RNA-associated E3 Ligase that selectively promotes ubiquitination of RBPs within RBP-mRNA complexes. This ubiquitination signal recruits HIP1, triggering the formation of MXLV, an autophagic vesicle that degrades translationally silent mRNP complexes. Genetic ablation of MX-H components in male germ cells disrupts spermiogenesis, leading to the accumulation of mRNP aggregates and male infertility. Intriguingly, we discovered that this germline-restricted pathway is aberrantly activated in Gastric Cancer cells, where MXLV biogenesis promotes tumor progression. The strict restriction of MXLV to male germ cells under physiological conditions may provide a unique therapeutic window, suggesting that targeting this pathway could suppress tumor progression while minimizing adverse effects on normal physiological functions. Our work establishes MXLV as a specialized vesicular structure essential for cellular remodeling during development and reveals how a germline-specific membrane trafficking system is co-opted in pathological proteome remodeling in Gastric Cancer.

Keywords
Autophagy; Cancer; MXLV; Spermiogenesis; Ubiquitination; mRNAderepression.
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