Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 9 (12)

Subcellular Trafficking of the Papillomavirus Genome During Initial Infection: The Remarkable Abilities of Minor Capsid Protein L2

Affiliations
Review

Subcellular Trafficking of the Papillomavirus Genome During Initial Infection: The Remarkable Abilities of Minor Capsid Protein L2

Samuel K Campos. Viruses.

Abstract

Since 2012, our understanding of human papillomavirus (HPV) subcellular trafficking has undergone a drastic paradigm shift. Work from multiple laboratories has revealed that HPV has evolved a unique means to deliver its viral genome (vDNA) to the cell nucleus, relying on myriad host cell proteins and processes. The major breakthrough finding from these recent endeavors has been the realization of L2-dependent utilization of cellular sorting factors for the retrograde transport of vDNA away from degradative endo/lysosomal compartments to the Golgi, prior to mitosis-dependent nuclear accumulation of L2/vDNA. An overview of current models of HPV entry, subcellular trafficking, and the role of L2 during initial infection is provided below, highlighting unresolved questions and gaps in knowledge.

Keywords: HPV16; L2; fusion peptide; gamma secretase; human papillomavirus; membrane penetration; mitosis; retromer; subcellular trafficking; toxin; translocation; transmembrane domain.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Diagram of the L2 protein. Positions of key components are illustrated. Relative distances and positions are to scale. Chromatin binding mutations are bolded and underlined in red to highlight the residues that were substituted.
Figure 2
Figure 2
Early subcellular trafficking and uncoating. Internalized virions, primed by cleavage on the cell surface, enter the endolysosomal pathway and begin pH-dependent uncoating and L2 insertion/penetration. L2 recruitment of cytosolic sorting factors including sorting nexins (SNXs) and retromer modulates the trafficking pathway. Retromer binding is important for EE to LE/MVB transport. Retrograde transport of L2/vDNA from LE/MVBs to the trans-Golgi network (TGN) occurs in a furin-, cyclophilin- γ-sec-, and pH-dependent manner.
Figure 3
Figure 3
Post-TGN mitotic trafficking of L2/vDNA complex. Upon entry into mitosis, L2/vDNA remains vesicle-bound but loses coincidence with TGN markers. These L2/vDNA-containing vesicles likely travel along astral microtubules in the minus-end direction towards the centrosome, where they accumulate during prometaphase. The vesicles likely switch polarity and travel along the spindle microtubules in the plus-end direction to reach the host chromosomes by metaphase. Chromosome-bound L2/vDNA partitions with host chromosomes, eventually localizing to PML bodies of the daughter cells. Chromosome binding of L2/vDNA is through the chromatin binding region (CBR) of L2 and mutation of this region causes a block in translocation, with vesicular L2/vDNA becoming reabsorbed back into the nascent Golgi after mitosis. Chromosome-bound L2/vDNA may be in a membrane-bound vesiclular state, or may have penetrated the limiting membrane upon chromosome binding, further work is needed to clarify this stage of the HPV life cycle.
Figure 4
Figure 4
Topology models of L2 protrusion. Both models are consistent with published L2 immunofluorescence and trypsin susceptibility data [80]. (A) In the type-I model, the N-terminus remains lumenal with all ~400 residues downstream of the TMD being cytosolic to recruit sorting factors. L2-BirA would be expected to biotinylate substrate in this model, contradicting the actual data [51]. (B) In the double-pass model, both the N- and C-termini would be lumenal, with the bulk of L2 being cytosolic. L2-BirA would not be expected to biotinylate substrate as observed. However, the means by which L2 spans the membrane a second time is difficult to conceptualize, as the protein only has one TMD towards the N-terminus [79]. In vitro data suggest both the N- and C-termini are capable of non-speciific dsDNA binding through electrostatic interactions [12,14].

Similar articles

See all similar articles

Cited by 18 articles

See all "Cited by" articles

References

    1. Bzhalava D., Muhr L.S., Lagheden C., Ekstrom J., Forslund O., Dillner J., Hultin E. Deep sequencing extends the diversity of human papillomaviruses in human skin. Sci. Rep. 2014;4:5807. doi: 10.1038/srep05807. - DOI - PMC - PubMed
    1. Van Doorslaer K. Evolution of the papillomaviridae. Virology. 2013;445:11–20. doi: 10.1016/j.virol.2013.05.012. - DOI - PubMed
    1. Van Doorslaer K., Li Z., Xirasagar S., Maes P., Kaminsky D., Liou D., Sun Q., Kaur R., Huyen Y., McBride A.A. The papillomavirus episteme: A major update to the papillomavirus sequence database. Nucleic Acids Res. 2017;45:D499–D506. doi: 10.1093/nar/gkw879. - DOI - PMC - PubMed
    1. Doorbar J., Quint W., Banks L., Bravo I.G., Stoler M., Broker T.R., Stanley M.A. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30(Suppl. 5):F55–F70. doi: 10.1016/j.vaccine.2012.06.083. - DOI - PubMed
    1. Forman D., de Martel C., Lacey C.J., Soerjomataram I., Lortet-Tieulent J., Bruni L., Vignat J., Ferlay J., Bray F., Plummer M., et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;30(Suppl. 5):F12–F23. doi: 10.1016/j.vaccine.2012.07.055. - DOI - PubMed
Feedback