Target cell cyclophilins facilitate human papillomavirus type 16 infection.
Following attachment to primary receptor heparan sulfate proteoglycans (HSPG), human papillomavirus type 16 (HPV16) particles undergo conformational changes affecting the major and minor capsid proteins, L1 and L2, respectively. This results in exposure of the L2 N-terminus, transfer to uptake receptors, and infectious internalization. Here, we report that target cell cyclophilins, peptidyl-prolyl cis/trans isomerases, are required for efficient HPV16 infection. Cell surface cyclophilin B (CyPB) facilitates conformational changes in capsid proteins, resulting in exposure of the L2 N-terminus. Inhibition of CyPB blocked HPV16 infection by inducing noninfectious internalization. Mutation of a putative CyP binding site present in HPV16 L2 yielded exposed L2 N-terminus in the absence of active CyP and bypassed the need for cell surface CyPB. However, this mutant was still sensitive to CyP inhibition and required CyP for completion of infection, probably after internalization. Taken together, these data suggest that CyP is required during two distinct steps of HPV16 infection. Identification of cell surface CyPB will facilitate the study of the complex events preceding internalization and adds a putative drug target for prevention of HPV-induced diseases.
Bienkowska-Haba
Malgorzata
M
Department of Microbiology and Immunology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
Patel
Hetalkumar D
HD
Sapp
Martin
M
D002213:Capsid / Q000378:metabolism; D036022:Capsid Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000378:metabolism / Q000502:physiology*; D052161:Human papillomavirus 18 / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000517:prevention & control / Q000821:virology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D053585:Virus Attachment; D053586:Virus Internalization
D036022:Capsid Proteins; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; C081786:cyclophilin B; D021983:Cyclophilins