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J Cell Biol. 2018 Oct 1;217(10):3545-3559. doi: 10.1083/jcb.201804171. Epub 2018 Jul 13.

γ-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection.

Author information

1
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI.
2
Department of Genetics, Yale School of Medicine, New Haven, CT.
3
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI.
4
Department of Genetics, Yale School of Medicine, New Haven, CT daniel.dimaio@yale.edu.
5
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT.
6
Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT.
7
Yale Cancer Center, New Haven, CT.
8
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI btsai@umich.edu.

Abstract

Despite their importance as human pathogens, entry of human papillomaviruses (HPVs) into cells is poorly understood. The transmembrane protease γ-secretase executes a crucial function during the early stages of HPV infection, but the role of γ-secretase in infection and the identity of its critical substrate are unknown. Here we demonstrate that γ-secretase harbors a previously uncharacterized chaperone function, promoting low pH-dependent insertion of the HPV L2 capsid protein into endosomal membranes. Upon membrane insertion, L2 recruits the cytosolic retromer, which enables the L2 viral genome complex to enter the retrograde transport pathway and traffic to the Golgi en route for infection. Although a small fraction of membrane-inserted L2 is also cleaved by γ-secretase, this proteolytic event appears dispensable for HPV infection. Our findings demonstrate that γ-secretase is endowed with an activity that can promote membrane insertion of L2, thereby targeting the virus to the productive infectious pathway.

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