PROTEIN-DISPOSAL machinery inside the nucleus of human sperm has been mapped in unprecedented detail, revealing specialised structures that may play important roles in sperm development and fertilisation.
Using advanced imaging techniques, researchers discovered that proteasomes, cellular machines responsible for breaking down proteins, cluster inside previously poorly understood cavities within the sperm nucleus. The findings could improve understanding of the molecular processes underpinning male fertility.
Proteasomes are molecular complexes that remove damaged or unnecessary proteins and help maintain normal cellular function. They are known to be important during sperm development and fertilisation, but their organisation and composition within the mature sperm nucleus have remained unclear.
Researchers used cryo-electron tomography, a technique capable of producing detailed three-dimensional images of cellular structures, to examine mature human sperm.
Human sperm from more than 25 donors were used across the study, alongside human testicular tissue from more than 10 donors. Researchers also examined mouse sperm to investigate whether similar structures occurred across species.
The team focused on cavities within the sperm nucleus known as nuclear lacunae. These spaces lack DNA and have previously been linked to chromatin organisation, sperm motility, and fertility outcomes, although their precise contents and function have been uncertain.
The researchers discovered large numbers of proteasomes concentrated within these DNA-free nuclear cavities.
Three types of proteasome complexes were identified. The vast majority, 94.4%, were 20S core proteasomes, while 5.3% consisted of 20S proteasomes capped by a single PA200 activator. A further 0.3% were capped by PA200 at both ends.
PA200 is particularly relevant to reproduction because it helps regulate the breakdown of proteins during sperm development.
Further examination of human testicular tissue showed that proteasomes became concentrated in the nucleus following meiosis, during the spermatid stage when immature male germ cells undergo extensive changes to develop into sperm.
Researchers also discovered a previously unidentified form of α4s, a testis-specific component of the proteasome that is considered important for sperm development and fertility.
High-resolution structural analysis provided additional information about how these sperm-specific proteasomes process proteins and how PA200 enhances their activity.
The findings provide a new picture of how protein degradation is organised within human sperm and could help researchers better understand several processes required for successful reproduction.
During sperm development, the DNA inside the nucleus undergoes extensive repackaging. Most histones, proteins around which DNA is normally wrapped, are removed and replaced with protamines, allowing the paternal genome to become extremely compact.
Proteasomes are thought to contribute to this process by helping remove histones. The researchers also propose that proteasomes retained within mature sperm could have a role after fertilisation, potentially helping to unpack the paternal genome once sperm enters the egg.
However, the study did not investigate whether differences in these structures predict infertility or pregnancy outcomes. The human sperm samples were obtained from donors rather than patients with diagnosed infertility, meaning direct clinical implications cannot yet be established.
Further research will therefore be needed to determine how disruption of these specialised proteasomes affects human fertility.
Nevertheless, the findings provide a detailed structural framework for investigating how protein regulation contributes to sperm development, fertilisation, and the earliest stages of embryonic development.
Reference
Kolata P et al. Molecular architecture and spatial organization of proteasomes in the human sperm nucleus. Nat Struct Mol Biol. 2026.
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