Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation.

APOBEC3 (A3) mutation signatures have been observed in a variety of human cancer genomes, including those of cervical and head and neck cancers caused by human papillomavirus (HPV) infection. However, the driving forces that promote off-target A3 activity remain mostly unclear. Here, we report a mechanism for the dramatic increase of A3A protein levels in HPV-positive keratinocytes. We show that expression of the viral protein E7 from high-risk HPVs, but not E7 from low-risk HPVs, significantly prolongs the cellular half-life of A3A protein in human keratinocytes and HPV-positive cancer cell lines. We have mapped several residues within the cullin 2 (CUL2) binding motif of HPV16 E7 as being important for mediating A3A protein stabilization. Furthermore, we provide direct evidence that both A3A and HPV16 E7 interact with CUL2, suggesting that the E7-CUL2 complex formed during HPV infection may regulate A3A protein levels in the cell. Using an in vitro cytidine deaminase assay, we show that E7-stabilized A3A remains catalytically active. Taken together, our findings suggest that the HPV oncoprotein E7 dysregulates endogenous A3A protein levels and thus provides novel mechanistic insight into cellular triggers of A3 mutations in HPV-positive cancers.IMPORTANCE Human papillomavirus (HPV) is causally associated with over 5% of all human malignancies. Several recent studies have shown that a subset of cancers, including HPV-positive head and neck and cervical cancers, have distinct mutational signatures potentially caused by members of the APOBEC3 cytidine deaminase family. However, the mechanism that induces APOBEC3 activity in cancer cells is poorly understood. Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner. Interestingly, the HPV E7-stabilized A3A protein maintains its deaminase activity. These findings provide a new insight into cancer mutagenesis enhanced by virus-induced A3A protein stabilization.

Warfighter Personal Protective Equipment and Combat Wounds.

BACKGROUND: Personal protective equipment (PPE) is crucial to force protection and preservation. Innovation in PPE has shifted injury patterns, with protected body regions accounting for decreased proportions of battlefield trauma relative to unprotected regions. Little is known regarding the PPE in use by warfighters at the time of injury. METHODS: We queried the Prehospital Trauma Registry (PHTR) for all encounters from 2003-2019. This is a sub-analysis of casualties with documented PPE at the time of medical encounter. When possible, encounters were linked to the Department of Defense Trauma Registry (DODTR) for outcome data. Serious injuries are defined as an abbreviated injury scale of 3 or greater. RESULTS: Of 1,357 total casualty encounters in the PHTR, 83 were US military with documented PPE. We link 62 of this cohort to DODTR. The median composite Injury Severity Score (ISS) was 6 (Interquartile range (IQR) 4-21), and 11 casualties (18%) had an ISS >25. The most seriously injured body regions were the extremities (21%), head/neck (16%), thorax (16%), and abdomen (10%). PPE worn at time of injury included helmet (91%), eye protection (73%), front (75%) and rear plates (77%), left/right plates (65%), tactical vest (46%), groin protection (12%), neck protection (6%), pelvic shield (3%), and deltoid protection (3%). CONCLUSION: Our data set demonstrates that the extremities were the most commonly injured body region, followed by head/neck, and thorax. PPE designed for the extremities and neck are also among the least commonly worn protective equipment.