Abstract
Simple SummaryThe von Hippel–Lindau (pVHL) tumor suppressor is a protein that regulates the normal cell adaptation to low oxygen concentrations. When its function is altered by inherited or acquired mutation pVHL becomes causative of a familiar predisposition to develop different types of cancers. Besides this role, pVHL is also thought to have other relevant cell functions, and studies in mice demonstrated that this protein is crucial for correct testis development and sperm maturation. By scanning the testis-specific library, we identified 55 novel proteins that interact with the human pVHL, with many of them directly participating in metabolic pathways frequently altered in cancer. Furthermore, our results suggest that pVHL may be also important for correct gonad function in men.Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. The male mice model carrying VHL gene conditional knockout presents significant abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles. Here we aimed to explore whether pVHL could have a similar role in humans by performing a testis-tissue library screening complemented with in-depth bioinformatics analysis. We identified 55 novel pVHL binding proteins directly involved in spermatogenesis, cell differentiation and reproductive metabolism. In addition, computational investigation of these new interactors identified multiple pVHL-specific binding motifs and demonstrated that somatic mutations described in human cancers reside in these binding regions. Collectively, these findings suggest that, in addition to its role in cancer formation, pVHL may also be pivotal in normal gonadal development in humans.
Highlights
The von Hippel–Lindau (VHL) disease (OMIM number 193300) is a rare autosomal dominantly inherited genetic disorder [1] with an incidence of 1:36,000 live births and high penetrance of >90% by age 65 with a mean age at tumor diagnosis of 26 [2]
We identified 55 novel testis-specific pVHL30 interactors, with multiple proteins directly involved in spermatogenesis and reproductive metabolism, and which play a role in cancer formation
We found proteins regulating spermatogenesis, such as the Piwi-like protein 4 (PIWIL4), spermatogenic leucine zipper protein 1 (SPZ1) and spermatogenesis-associated protein 22 (SPATA22), indicating that pVHL30 could be functionally linked to sperm cell proliferation and differentiation in humans
Summary
The von Hippel–Lindau (VHL) disease (OMIM number 193300) is a rare autosomal dominantly inherited genetic disorder [1] with an incidence of 1:36,000 live births and high penetrance of >90% by age 65 with a mean age at tumor diagnosis of 26 [2]. Male mice carrying VHL conditional knockout present abnormalities in testis development, reduced sperm count, impaired spermatogenesis and infertility, besides altered vascularization in multiple organs which is a conventional marker of nonfunctional pVHL [19]; 25%–60% of VHL male patients develop epididymal papillary cystadenomas [20,21], an otherwise rare form of neoplasm affecting male reproductive organs [22]. In contrast with the VHL murine model, no infertility or defect of spermatogenesis are reported in humans except for mechanical obstruction of seminal ducts due to epididymal cysts. PVHL is required for the correct cilia formation [23], while it is well understood that multiple male infertility syndromes arise from congenital defects in ciliogenesis [24]. Defects in ciliogenesis are reported in cancer and linked to deregulation of the cellular response to signals from multiple pathways [25,26]
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