Ubiquitin-Proteasome System in Spermatogenesis and Male Infertility

The ubiquitin-proteasome system (UPS) orchestrates protein homeostasis during the elaborate series of events that convert spermatogonial stem cells into mature spermatozoa. Ubiquitin ligases tag regulatory proteins with chains of ubiquitin, marking them for selective recognition and processing by the proteasome, while deubiquitinases (DUBs) rescue or remodel substrates by removing ubiquitin moieties. This dynamic balance ensures timely progression through mitotic renewal, meiotic recombination, cytoplasmic remodelling and chromatin remodelling. Disruption of UPS components can impair gamete morphology, motility and genome integrity, contributing to idiopathic and genetically driven forms of male infertility. By defining stage-specific proteasome isoforms, specialised E3 ligase complexes and germ-cell-enriched DUBs, research has illuminated how proteostasis underpins chromosomal synapsis, spermatid individualisation and cytoplasmic clearance. Understanding these pathways carries global significance for the diagnosis of infertility, the development of non-hormonal male contraceptives and the identification of biomarkers predictive of reproductive outcomes.

Research from Nature Portfolio

A mouse model carrying a mutation in the X-linked deubiquitinase gene Usp26 has revealed that the impact of DUB deficiency on fertility is strongly influenced by genetic background. Males bearing the Usp26 mutation on a DBA/2 strain exhibited testicular atrophy, defective chromosomal synapsis during pachynema and reduced spermatid counts, whereas the same mutation on a C57BL/6 background produced milder phenotypes. The study uncovered increased apoptosis of metaphase spermatocytes and malformed sperm heads, highlighting the essential role of USP26 in meiotic progression and spermatid maturation. These findings underscore how DUB mutations can underlie human infertility and may interact with modifier loci to shape reproductive phenotypes.

Ubiquitin-Proteasome System in Spermatogenesis and Male Infertility publication trend

The graph below shows the total number of articles in ubiquitin-proteasome system in spermatogenesis and male infertility across all publications each year (not limited to Nature Index journals).

Technical terms

Ubiquitination: Covalent attachment of ubiquitin molecules to a substrate protein, marking it for proteasomal degradation or functional modulation.

Proteasome: A multisubunit protease complex that recognises and degrades ubiquitinated proteins into short peptides.

E3 ubiquitin ligase: An enzyme that confers substrate specificity by catalysing the transfer of ubiquitin from an E2 conjugating enzyme to target proteins.

Deubiquitinase (DUB): A protease that removes ubiquitin from proteins, thereby regulating degradation, trafficking and signalling.

Spermatogenesis: The sequential developmental process by which spermatogonial stem cells undergo mitosis, meiosis and spermiogenesis to produce mature sperm.

References

1. Ubiquitin-Proteasome System–Regulated Protein Degradation in Spermatogenesis. Cells (2022).
2. Usp26 mutation in mice leads to defective spermatogenesis depending on genetic background. Scientific Reports (2019).
3. Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells. Cells (2021).
4. Role of the Ubiquitin Ligase RNF149 in the Development of Rat Neonatal Gonocytes. Frontiers in Endocrinology (2022).