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A Peptide Derived from Sorting Nexin 1 Inhibits HPV16 Entry, Retrograde Trafficking, and L2 Membrane Spanning
Shuaizhi Li1,2, Zachary L Williamson1,2,3,4,5,6,7,8, Matthew A Christofferson1,4
1Department of Immunobiology, University of Arizona, Tucson, AZ USA.
Abstract:
High risk human papillomavirus (HPV) infection is responsible for 99% of cervical cancers and 5% of all human cancers worldwide. HPV infection requires the viral genome (vDNA) to gain access to nuclei of basal keratinocytes of epithelium. After virion endocytosis, the minor capsid protein L2 dictates the subcellular retrograde trafficking and nuclear localization of the vDNA during mitosis. Prior work identified a cell-permeable peptide termed SNX1.3, derived from the BAR domain of sorting nexin 1 (SNX1), that potently blocks the retrograde and nuclear trafficking of EGFR in triple negative breast cancer cells. Given the importance of EGFR and retrograde trafficking pathways in HPV16 infection, we set forth to study the effects of SNX1.3 within this context. SNX1.3 inhibited HPV16 infection by both delaying virion endocytosis, as well as potently blocking virion retrograde trafficking and Golgi localization. SNX1.3 had no effect on cell proliferation, nor did it affect post-Golgi trafficking of HPV16. Looking more directly at L2 function, SNX1.3 was found to impair membrane spanning of the minor capsid protein. Future work will focus on mechanistic studies of SNX1.3 inhibition, and the role of EGFR signaling and SNX1- mediated endosomal tubulation, cargo sorting, and retrograde trafficking in HPV infection.
Insights
A novel peptide, SNX1.3, effectively inhibits human papillomavirus (HPV) infection by blocking viral entry and intracellular trafficking. This discovery offers a potential new strategy for preventing HPV-related cancers.
Area of Science:
- Virology
- Cell Biology
- Cancer Research
Background:
- High-risk human papillomavirus (HPV) causes nearly all cervical cancers and a significant portion of other human cancers.
- HPV infection necessitates viral genome (vDNA) delivery to basal keratinocyte nuclei, a process mediated by the minor capsid protein L2.
- Retrograde trafficking and nuclear localization are crucial steps in HPV infection, involving pathways similar to those affected by sorting nexin 1 (SNX1).
Purpose of the Study:
- To investigate the effect of the cell-permeable peptide SNX1.3 on human papillomavirus type 16 (HPV16) infection.
- To determine if SNX1.3 can inhibit HPV infection by targeting retrograde trafficking pathways.
Main Methods:
- Utilized SNX1.3, a peptide derived from sorting nexin 1 (SNX1), known to block retrograde trafficking of EGFR.
- Assessed the impact of SNX1.3 on HPV16 virion endocytosis, retrograde trafficking, Golgi localization, and L2 protein function.
- Monitored cell proliferation and post-Golgi trafficking to evaluate SNX1.3's specificity.
Main Results:
- SNX1.3 significantly inhibited HPV16 infection by delaying virion endocytosis.
- SNX1.3 potently blocked HPV16 virion retrograde trafficking and Golgi localization.
- The peptide impaired the membrane-spanning function of the L2 protein without affecting cell proliferation or post-Golgi trafficking.
Conclusions:
- SNX1.3 is a potent inhibitor of HPV16 infection, acting at multiple stages including endocytosis and retrograde trafficking.
- SNX1.3's mechanism involves interference with the L2 capsid protein's function.
- Further research into SNX1.3, EGFR signaling, and SNX1-mediated trafficking could yield novel therapeutic strategies against HPV infections.
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