The KIF6‐RBP Complex Orchestrates mRNA Transport Required for Sperm Flagellar Assembly

ABSTRACT The precise assembly of the sperm flagellum is essential for male fertility and has long been ascribed to kinesin‐2–driven intraflagellar transport (IFT) of protein cargoes. However, during late spermiogenesis, when transcription activity is largely silenced, how the spatiotemporally regulated delivery of flagellar components remains poorly understood. Here, we systematically screened kinesin genes in asthenozoospermic patients and identified two homozygous deleterious KIF6 variants in unrelated men characterized by complete sperm immotility. Mouse models carrying the corresponding mutations recapitulated the human infertility phenotypes. Multi‐omics analyses revealed that most testicular mRNAs remained largely unchanged in Kif6 M1/M1 mice, whereas proteins involved in axonemal organization and energy metabolism were markedly reduced. Mechanistically, KIF6 interacts with the RNA‐binding proteins (RBPs) FMRP and FXR1 to assemble mRNP transport complexes that ferry transcripts encoding flagellar structural proteins (e.g., DNALI1) and metabolic enzymes (e.g., HK1). Impaired KIF6 function compromises mRNP trafficking to the developing flagellum, reducing flagellar transcript levels and ultimately causing decreased protein abundance and defective flagellar function. Collectively, we identify KIF6 as a key regulator of mRNA transport during spermiogenesis. It interacts with RBPs through a novel IFT‐like pathway to deliver mRNAs essential for flagellar biogenesis, redefining the traditional protein‐centric IFT paradigm.