Keratinocyte-secreted laminin 5 can function as a transient receptor for human papillomaviruses by binding virions and transferring them to adjacent cells.
Human papillomaviruses (HPVs) replicate only in the terminally differentiating epithelium of the skin and mucosa. While infection of basal keratinocytes is considered a requirement for permissive infection, it remains unclear whether virions can specifically target basal cells for adsorption and uptake following epithelial wounding. We present evidence that HPV binds specifically to laminin 5 (LN5), a component of the extracellular matrix (ECM) secreted by migrating and basal keratinocytes. HPV type 11 capsids colocalized with LN5 in the ECM secreted by vaginal keratinocytes. Binding of both virions and virus-like particles to purified LN5 and to the LN5-rich ECM secreted by cultured keratinocytes was effectively blocked by pretreatment with anti-LN5 antibodies. HPV capsid binding to human cervical mucosa sections included the basement membrane which contains LN5. Cultured keratinocytes expressing alpha6 integrin, a transmembrane protein known to bind LN5, were readily infected by virions preadsorbed to LN5-containing substrates, whereas mutant keratinocytes lacking alpha6 integrin were relatively resistant to infection via this route. These findings suggest a model of natural HPV infection in which proliferating keratinocytes expressing alpha6 integrin at the site of epithelial wounding might be targeted by virions adsorbed transiently to LN5 secreted by migrating keratinocytes.
Culp
Timothy D
TD
The Jake Gittlen Cancer Research Foundation, Milton S. Hershey Medical Center, Pennsylvania State University, 500 University Drive, Hershey, PA 17033-2390, USA.
Budgeon
Lynn R
LR
Marinkovich
M Peter
MP
Meneguzzi
Guerrino
G
Christensen
Neil D
ND
D000818:Animals; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002584:Cervix Uteri / Q000166:cytology / Q000473:pathology / Q000821:virology; D002522:Chlorocebus aethiops; D005109:Extracellular Matrix / Q000378:metabolism / Q000821:virology; D005260:Female; D052140:Human papillomavirus 11 / Q000378:metabolism; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D009092:Mucous Membrane / Q000473:pathology / Q000821:virology; D027383:Papillomaviridae / Q000378:metabolism*; D011485:Protein Binding; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D039503:Integrin alpha6; D000097794:Kalinin