Papillomaviruses and Endocytic Trafficking

Abstract

Endocytic trafficking plays a major role in transport of incoming human papillomavirus (HPVs) from plasma membrane to the trans Golgi network (TGN) and ultimately into the nucleus. During this infectious entry, several cellular sorting factors are recruited by the viral capsid protein L2, which plays a critical role in ensuring successful transport of the L2/viral DNA complex to the nucleus. Later in the infection cycle, two viral oncoproteins, E5 and E6, have also been shown to modulate different aspects of endocytic transport pathways. In this review, we highlight how HPV makes use of and perturbs normal endocytic transport pathways, firstly to achieve infectious virus entry, secondly to produce productive infection and the completion of the viral life cycle and, finally, on rare occasions, to bring about the development of malignancy.

Keywords: HPV; endocytic machinery; retriever; retromer; sorting nexins; viral capsid proteins; viral oncoproteins.

Figure 1

Schematic diagram of HPV intracellular trafficking to the TGN. (A) Following endocytosis, uncoating of papillomaviruses is triggered by acidification of the late endosome. Endosomes as they mature exhibit tubulation. L2/vDNA segregates from most of the L1, which is then degraded in the lysosome. L2/vDNA along with a small amount of L1 enters the TGN with the help of cellular sorting factors. The dashed box shows how the retromer and retriever complexes might cooperate in HPV infection, which is shown in more detail in panel B. (B) Prior to the entry of viral cargo to the TGN, L2 binds SNX27, retromer and SNX17 which is part of the retriever complex. The ER makes contact points with endosomes, Golgi and plasma membrane using integral ER VAP protein.

Figure 1

Schematic diagram of HPV intracellular trafficking to the TGN. (A) Following endocytosis, uncoating of papillomaviruses is triggered by acidification of the late endosome. Endosomes as they mature exhibit tubulation. L2/vDNA segregates from most of the L1, which is then degraded in the lysosome. L2/vDNA along with a small amount of L1 enters the TGN with the help of cellular sorting factors. The dashed box shows how the retromer and retriever complexes might cooperate in HPV infection, which is shown in more detail in panel B. (B) Prior to the entry of viral cargo to the TGN, L2 binds SNX27, retromer and SNX17 which is part of the retriever complex. The ER makes contact points with endosomes, Golgi and plasma membrane using integral ER VAP protein.

Figure 2

Model representing possible molecular mechanisms by which E5 manipulates trafficking pathways and potentially predisposes the infected cell towards cancer development. E5 inhibits the transport of immune receptors (MHCI, MHCII, CD1d) to the cell surface, and prevents clearance of infected cells by the immune response (1). It also upregulates the cell surface expression of caveolin-1 and ganglioside GM1 (2). Moreover, E5 can inhibit endosome acidification (3) or the trafficking from early to late endosomes (4) which may promote recycling of EGFR to the cell surface and lead to aberrant proliferation (5). Note that E5 localizes primarily to the endoplasmatic reticulum (ER), but it can also be found in the Golgi apparatus, in perinuclear regions and on the plasma membrane.

Figure 3

Working model showing the possible mechanism of modulation of SNX27-retromer mediated cargo recycling by HPV E6. After internalization, cargoes containing a PDZ-binding motif (PBM) bind to a PDZ domain of SNX27. SNX27 serves as an adaptor linking its cargoes to the endosomal tubules through its interaction. Association within the SNX27-retromer-WASH complex directs the cargoes towards recycling to the plasma membrane. The E6-SNX27 interaction may be a transient step in the handover in the SNX27-retromer complex for cargo binding, which may in turn promote faster recycling or inhibit recycling of certain PBM-containing cargoes. It is still unknown if E6 helps recruit SNX27 to certain endocytic compartments or competes for binding with SNX27 cargoes. Solid line shows the role of the SNX27-retromer complex in cargo recycling. The dashed line shows how E6 might affect this.