Human Papillomavirus Hijacks the Dual Endosome-Golgi Membrane Systems During Cell Entry

Abstract

Human papillomavirus (HPV) is a common human pathogen, infecting the majority of individuals by adulthood. Although most HPV infections resolve spontaneously, persistent infection with certain HPV types contributes to cervical, anogenital, and oropharyngeal cancers, and is also responsible for a wide variety of warts. Despite the significant impact of HPV on human health, many details of its cellular entry mechanism remain a mystery.

From the host cell surface, HPV is internalized by endocytosis, delivered to the endosome, and then transported to the Golgi apparatus. Upon mitosis, HPV exits the Golgi and enters the nucleus during mitotic nuclear envelope breakdown. Once in the nucleus, the viral genome is delivered to the nucleoplasm and replication ensues. Throughout this process, HPV remains largely protected within organelles and transport vesicles, presumably to avoid detection by the host cell. How then does HPV direct itself along the proper route for infection? This dissertation provides a mechanistic roadmap for how HPV transits two distinct organelles – the endosome and the Golgi – en route to the nucleus to establish infection, with particular focus on the oncogenic HPV type 16 (HPV16).

Specifically, this dissertation demonstrates how the cytosolic protein p120 catenin targets HPV to the endosomal membrane protein gamma-secretase. This is a critical step because gamma-secretase promotes insertion of the viral capsid protein L2 across the endosome membrane. Membrane insertion exposes a portion of L2 to the cytosol, enabling this viral protein to recruit cytosolic sorting factors that target the virus to the Golgi en route for infection. Hence, these studies identify a new host factor, p120 catenin, that facilitates the recruitment of a viral protein to the host gamma-secretase, a key event that drives the virus along a productive entry pathway.

Upon Golgi arrival, HPV must transit this complex organelle to cause infection. This dissertation reveals the mechanism by which HPV transits the Golgi apparatus – by directly engaging the COPI sorting complex. Direct binding of HPV to the COPI retrograde sorting complex is essential for HPV to exit the Golgi and reach the nucleus. Though COPI is a highly conserved cellular complex, this is the first evidence of a virus that acts as a cargo for COPI during viral entry. These studies provide mechanistic insight into how HPV hijacks classic retrograde trafficking machinery to support its own vesicular transport through the Golgi.