The high-risk HPV E6 target scribble (hScrib) is required for HPV E6 expression in cervical tumour-derived cell lines.

The ability of high-risk HPV E6 oncoproteins to target cellular proteins which harbor PDZ domains is believed to play an important role in the virus life cycle and to influence the ability of these viruses to bring about malignant transformation. Whilst many of these PDZ proteins are potential tumour suppressors, involved in the control of cell polarity and cell-contact, recent studies suggest that mislocalisation or overexpression might result in the emergence of oncogenic functions. This has been shown most clearly for two E6 targets, hDlg and hScrib. In this study we show that hScrib plays such a role in HeLa cells, where its expression is required for maintaining high levels of HPV-18 E6 protein. Loss of hScrib has no effect on E6 stability but results in lower levels of E6 transcription and a reduced rate of E6 translation. We further show that, in the context of cervical tumour-derived cell lines, both hScrib and E6 cooperate in the activation of the S6 kinase signaling pathway, and thereby contribute towards maintaining high rates of protein translation. These results indicate that the residual hScrib that is present within HPV transformed cells is pro-oncogenic, and highlights the dual functions of E6 cell polarity targets.

Stabilization of HPV16 E6 protein by PDZ proteins, and potential implications for genome maintenance.

The E6 protein from high-risk human papillomaviruses appears necessary for persistence of viral episomes in cells but the underlying mechanism is unclear. E6 has many activities, including its ability to bind and degrade PDZ domain-containing proteins, such as hScrib. However little is known about the role of these interactions for E6 function and the viral life cycle. We now show that the levels of expression of wild-type E6 are increased in the presence of hScrib whilst a mutant E6 protein lacking the PDZ-binding motif is found at lower levels as it is turned over more rapidly by the proteasome. This correlates with an inability of genomes containing this mutation to be maintained as episomes. These results show that E6 association with certain PDZ domain-containing proteins can stabilize the levels of E6 expression and provides one explanation as to how the PDZ-binding capacity of E6 might contribute to genome episomal maintenance.

A genome-wide analysis in Anopheles gambiae mosquitoes reveals 46 male accessory gland genes, possible modulators of female behavior.

The male accessory glands (MAGs) of many insect species produce and secrete a number of reproductive proteins collectively named Acps. These proteins, many of which are rapidly evolving, are essential for male fertility and represent formidable modulators of female postmating behavior. Upon copulation, the transfer of Acps has been shown in Drosophila and other insects to trigger profound physiological and behavioral changes in females, including enhanced ovulation/oviposition and reduced mating receptivity. In Anopheles gambiae mosquitoes, the principal vectors of human malaria, experimental evidence clearly demonstrates a key role of MAG products in inducing female responses. However, no Acp has been experimentally identified to date in this or in any other mosquito species. In this study we report on the identification of 46 MAG genes from An. gambiae, 25 of which are male reproductive tract-specific. This was achieved through a combination of bioinformatics searches and manual annotation confirmed by transcriptional profiling. Among these genes are the homologues of 40% of the Drosophila Acps analyzed, including Acp70A, or sex peptide, which in the fruit fly is the principal modulator of female postmating behavior. Although many Anopheles Acps belong to the same functional classes reported for Drosophila, suggesting a conserved role for these proteins in mosquitoes, some represent novel lineage-specific Acps that may have evolved to perform functions relevant to Anopheles reproductive behavior. Our findings imply that the molecular basis of Anopheles female postmating responses can now be studied, opening novel avenues for the field control of these important vectors of human disease.