The Cellular Endosomal Protein Stannin Inhibits Human Papillomavirus Entry

Human papillomaviruses (HPVs) are the most common sexually transmitted viruses and one of the most important infectious causes of cancers worldwide. While prophylactic vaccines are effective against certain strains of HPV, established infections still cause deadly cancers in both men and women. HPV traffics to the nucleus via the retrograde transport pathway, but the mechanism of intracellular transport of nonenveloped viruses such as HPV is incompletely understood. Using an overexpression screen, we identify several novel genes that control HPV16 entry. We focused on the mechanism by which one of the screen hits, stannin, blocks HPV16 infection. Stannin has not been previously implicated in virus entry. We show that stannin is constitutively expressed in human keratinocytes, and its basal levels inhibit entry by HPV16. Overexpression of stannin specifically inhibits infection by several HPV types, but not other non-enveloped viruses tested. Stannin is localized to the endolysosomal compartment and does not affect HPV16 binding to cells, uptake, or uncoating, but diverts HPV away from the trans-Golgi network and directs it to the lysosome where it is degraded. We further show that SNN interacts with L1 major capsid protein and that this interaction is modulated by the retromer binding motifs in the C-terminus of the minor capsid protein L2. Our findings shed light on novel cellular factors that control HPV entry.