γ-secretase facilitates retromer-mediated retrograde transport.

The retromer complex mediates retrograde transport of protein cargos from endosomes to the trans-Golgi network (TGN). γ-secretase is a multisubunit protease that cleaves the transmembrane domain of its target proteins. Mutations in genes encoding subunits of retromer or γ-secretase can cause familial Alzheimer disease (AD) and other degenerative neurological diseases.

Human Papillomavirus L2 Capsid Protein Stabilizes γ-Secretase during Viral Infection.

Intracellular trafficking of human papillomavirus (HPV) during virus entry requires γ-secretase, a cellular protease consisting of a complex of four cellular transmembrane (TM) proteins. γ-secretase typically cleaves substrate proteins but it plays a non-canonical role during HPV entry. γ-secretase binds to the HPV minor capsid protein L2 and facilitates its insertion into the endosomal membrane.

Retromer stabilizes transient membrane insertion of L2 capsid protein during retrograde entry of human papillomavirus.

Retromer, a cellular protein trafficking complex, sorts human papillomaviruses (HPVs) into the retrograde pathway for transport of HPV to the nucleus during virus entry. Here, we conducted a protein modulation screen to isolate four artificial transmembrane proteins called traptamers that inhibit different steps of HPV entry. By analyzing cells expressing pairs of traptamers, we ordered the trafficking steps during entry into a coherent pathway.

TBC1D5-Catalyzed Cycling of Rab7 Is Required for Retromer-Mediated Human Papillomavirus Trafficking during Virus Entry.

During virus entry, human papillomaviruses are sorted by the cellular trafficking complex, called retromer, into the retrograde transport pathway to traffic from the endosome to downstream cellular compartments, but regulation of retromer activity during HPV entry is poorly understood. Here we selected artificial proteins that modulate cellular proteins required for HPV infection and discovered that entry requires TBC1D5, a retromer-associated, Rab7-specific GTPase-activating protein. Binding of retromer to the HPV L2 capsid protein recruits TBC1D5 to retromer at the endosome membrane, which then stimulates hydrolysis of Rab7-GTP to drive retromer disassembly from HPV and delivery of HPV to the retrograde pathway.

Papillomaviruses Go Retro.

Human papillomaviruses are important pathogens responsible for approximately 5% of cancer as well as other important human diseases, but many aspects of the papillomavirus life cycle are poorly understood. To undergo genome replication, HPV DNA must traffic from the cell surface to the nucleus. Recent findings have revolutionized our understanding of HPV entry, showing that it requires numerous cellular proteins and proceeds via a series of intracellular membrane-bound vesicles that comprise the retrograde transport pathway.

The cellular endosomal protein stannin inhibits intracellular trafficking of human papillomavirus during virus entry.

Human papillomaviruses (HPVs) are the most common sexually transmitted viruses and one of the most important infectious causes of cancers worldwide. While prophylactic vaccines are effective against certain strains of HPV, established infections still cause deadly cancers in both men and women. HPV traffics to the nucleus via the retrograde transport pathway, but the mechanism of intracellular transport of non-enveloped viruses such as HPV is incompletely understood.