Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening

Abstract

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.

Role of Ubiquitin Ligases and Conjugases in Targeted Cancer Therapy

“…The regulation of the transcriptional factor KAP1, also known as TRIM28 (a ubiquitin ligase), by SMURF2, another ubiquitin ligase, in breast cancer cells was shown by Shah et al [ 15 ]. Mutations of substrates binding motifs of VHL, a ubiquitin ligase adaptor that functions as an E3 substrate recognition protein, were reported by Faclconieri et al and found to be associated with VHL tumors [ 16 ]. The discovery of an inhibitor of the deubiquitinase OTUD7B by Chen and colleagues provides evidence for a potential therapeutic target in leukemia cells [ 17 ].…”