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

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.