# NXT2 is a key component of the RNA nuclear export factor complex in the human testis and essential for spermatogenesis

## TL;DR

NXT2 is a key protein in RNA transport in human testis, and its mutations cause male infertility by disrupting germ cell development.

## Contribution

NXT2 is identified as a novel component of the RNA export machinery in human testis, essential for spermatogenesis.

## Key findings

- NXT2 interacts with NXF1, NXF2, NXF3, and nuclear pore complex proteins in the testis.
- Loss-of-function variants in NXT2 and NXF3 are linked to impaired germ cell development and male infertility.
- NXT2 deficiency affects early germ cell development, while NXF3 deficiency impacts later stages of spermatogenesis.

## Abstract

In eukaryotes, the nucleocytoplasmic export of bulk poly(A)+-mRNAs through the nuclear pore complex is mediated by the ubiquitously expressed NXT1-NXF1 heterodimer. In humans, NXT1 has an X-chromosomal paralog, NXT2, which exhibits testis-enriched expression, suggesting a role in spermatogenesis. Here, we report the in vivo interaction of NXT2 with crucial components of the nuclear export machinery, including NXF1, the testis-specific NXF1 paralogs NXF2 and NXF3, and nuclear pore complex proteins. Binding to NXF2 and NXF3 is mediated by the NTF2-like domain of NXT2. By identifying infertile men with loss-of-function variants in NXT2 and NXF3, we link the impaired NXT2-NXF activity to disturbed germ cell development. The predominant absence of germ cells in men with NXT2 deficiency indicates its critical function already during fetal or first steps of germ cell development. In contrast, loss of NXF3 affects later stages of spermatogenesis, resulting in quantitatively and qualitatively impaired sperm production.

The study introduces NXT2 as a candidate gene for male infertility and shows that the encoded protein is involved in RNA nucleocytoplasmic transport in human testis by interacting with the RNA export factor NXF1 and proteins of the nuclear pore complex. NXT2 also interacts with the human testis-specific NXF1 paralogues NXF2 and NXF3. Mutations in NXT2 and NXF3 are linked to a disruption of nuclear export, leading to defective germ cell development and human male infertility.