Heterotetrameric annexin A2/S100A10 (A2t) is essential for oncogenic human papillomavirus trafficking and capsid disassembly, and protects virions from lysosomal degradation

Abstract

Human papillomavirus (HPV) entry into epithelial cells is independent of canonical endocytic pathways. Upon interaction with host cells, HPV establishes infection by traversing through an endocytic pathway that is clathrin- and caveolin-independent, but dependent on the annexin A2/S100A10 heterotetramer (A2t). We examined the contribution of monomeric annexin A2 (AnxA2) vs. A2t in HPV infection and endocytosis, and further characterized the role of these molecules in protein trafficking. We specifically show that cell surface A2t is not required for HPV attachment, and in the absence of A2t virion internalization remains clathrin-independent. Without A2t, viral progression from early endosomes to multivesicular endosomes is significantly inhibited, capsid uncoating is dramatically reduced, and lysosomal degradation of HPV is accelerated. Furthermore, we present evidence that AnxA2 forms a complex with CD63, a known mediator of HPV trafficking. Overall, the observed reduction in infection is less significant in the absence of S100A10 alone compared to full A2t, supporting an independent role for monomeric AnxA2. More broadly, we show that successful infection by multiple oncogenic HPV types is dependent on A2t. These findings suggest that A2t is a central mediator of high-risk HPV intracellular trafficking post-entry and pre-viral uncoating.

Annexin A2 extracellular translocation and virus interaction: A potential target for antivirus‐drug discovery

“…Furthermore, increased expression of annexin A2 on the surface of host cells upon exposure to HPV has been reported; annexin A2 forms complex with CD63 and facilitate HPV trafficking. It was further demonstrated that attenuation of annexin A2 may result in an impaired virus internalization, capsid uncoating, and exposed the viral particle to accelerated lysosomal degradation . Taken together this shows that annexin A2 served as an indispensable receptor molecule in HPV infection, involved in virus attachment, internalization, and intracellular trafficking.…”

Tetraspanin CD9 affects HPV16 infection by modulating ADAM17 activity and the ERK signalling pathway

“…To follow HPV16 during the early steps of virus entry, we performed immunofluorescence stainings of the major capsid protein L1 and CD63, a tetraspanin that accumulates with HPV16 capsids in multivesicular bodies (MVBs) [18,45]. As earlier described, control siRNA-treated HeLa cells showed prominent HPV16-CD63 colocalization in vesicular structures (Fig.…”

The Essential Role of anxA2 in Langerhans Cell Birbeck Granules Formation

“…We previously reported that this manipulation of LC by HPV is facilitated by the interaction with the annexin A2 S100A10 heterotetramer (A2t) [20]. Further investigation showed that A2t was directly involved in infectious trafficking of HPV virions [21]. In exploring the role of A2t in HPV-LC interactions, we made the interesting observation that BG structures were impacted by modulation of A2t expression, warranting further investigation into the relationship between A2t and BG formation.…”