2. Academic Validation
  3. A germline-specific vesicular structure licenses mRNA activation during spermiogenesis and is hijacked in gastric cancer

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

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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