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.
摘要:
高危型人乳头瘤病毒(HPV)感染是全球99%的宫颈癌和5%的所有人类癌症的原因。HPV感染需要病毒基因组(vDNA)才能进入上皮的基底角质形成细胞的细胞核。病毒内吞作用后,次要衣壳蛋白L2决定了有丝分裂期间vDNA的亚细胞逆行运输和核定位。先前的工作确定了一种称为SNX1.3的细胞可渗透肽,该肽来自分选连接蛋白1(SNX1)的BAR域,有效阻断三阴性乳腺癌细胞中EGFR的逆行和核运输。鉴于EGFR和逆行转运途径在HPV16感染中的重要性,我们着手在此背景下研究SNX1.3的影响。SNX1.3通过延缓病毒体内吞作用抑制HPV16感染,以及有效阻止病毒体逆行贩运和高尔基本地化。SNX1.3对细胞增殖没有影响,也不影响高尔基后HPV16的贩运。更直接地观察L2函数,发现SNX1.3损害了次要衣壳蛋白的跨膜。未来的工作将集中在SNX1.3抑制的机理研究,以及EGFR信号传导和SNX1-介导的内体插管的作用,货物分类,和HPV感染的逆行贩运。