The Known and Potential Intersections of Rab-GTPases in Human Papillomavirus Infections

Abstract

Papillomaviruses (PVs) were the first viruses recognized to cause tumors and cancers in mammalian hosts by Shope, nearly a century ago ( Shope and Hurst, 1933 ). Over 40 years ago, zur Hausen (1976) first proposed that human papillomaviruses (HPVs) played a role in cervical cancer; in 2008, he shared the Nobel Prize in Medicine for his abundant contributions demonstrating the etiology of HPVs in genital cancers. Despite effective vaccines and screening, HPV infection and morbidity remain a significant worldwide burden, with HPV infections and HPV-related cancers expected increase through 2040. Although HPVs have long-recognized roles in tumorigenesis and cancers, our understanding of the molecular mechanisms by which these viruses interact with cells and usurp cellular processes to initiate infections and produce progeny virions is limited. This is due to longstanding challenges in both obtaining well-characterized infectious virus stocks and modeling tissue-based infection and the replicative cycles in vitro . In the last 20 years, the development of methods to produce virus-like particles (VLPs) and pseudovirions (PsV) along with more physiologically relevant cell- and tissue-based models has facilitated progress in this area. However, many questions regarding HPV infection remain difficult to address experimentally and are, thus, unanswered. Although an obligatory cellular uptake receptor has yet to be identified for any PV species, Rab-GTPases contribute to HPV uptake and transport of viral genomes toward the nucleus. Here, we provide a general overview of the current HPV infection paradigm, the epithelial differentiation-dependent HPV replicative cycle, and review the specifics of how HPVs usurp Rab-related functions during infectious entry. We also suggest other potential interactions based on how HPVs alter cellular activities to complete their replicative-cycle in differentiating epithelium. Understanding how HPVs interface with Rab functions during their complex replicative cycle may provide insight for the development of therapeutic interventions, as current viral counter-measures are solely prophylactic and therapies for HPV-positive individuals remain archaic and limited.

Targeting Endosomal Recycling Pathways by Bacterial and Viral Pathogens

“…It has been known for some time that the cellular trafficking of HPV requires Rab7a ( Day et al, 2013 ; Lipovsky et al, 2013 ; Young et al, 2019 ). How Rab7a mediates HPV trafficking remained unclear until recently.…”

TBC1D5-Catalyzed Cycling of Rab7 Is Required for Retromer-Mediated Human Papillomavirus Trafficking during Virus Entry

“…HPV trafficking also requires Rab7B (Young et al, 2019;Day et al, 2013;Lipovsky et al, 2013). The Rab proteins are small guanosine triphosphatases (GTPases) that regulate intracellular membrane trafficking events by cycling between a membraneassociated guanosine triphosphate (GTP)-bound form and a cytosolic guanosine diphosphate (GDP)-bound form (Guerra and Bucci, 2016;Stroupe, 2018).…”

Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

“…Initial infection is targeted to keratinocytes in the basal epithelial layer; productive infection requires that cells remain mitotically active upon cellular differentiation for competent virus replication [27,28]. HPV gains access to target cells via microlesions generated in the skin or mucosa, and entry into the target cell requires a number of putative host receptor molecules, including heparan sulphate proteoglycans (HSPG) and α-6 integrins [29][30][31]. Binding of the major capsid protein L1 to cell receptors leads to exposure of the N-terminus of the minor capsid protein L2, allowing furin-mediated cleavage of L2 [32][33][34].…”