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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Capsid Proteins / genetics
  • Capsid Proteins / metabolism*
  • Endosomes / genetics
  • Endosomes / metabolism
  • Endosomes / pathology
  • Endosomes / virology
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / pathology
  • Golgi Apparatus / virology
  • HEK293 Cells
  • HeLa Cells
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Intracellular Membranes / metabolism
  • Intracellular Membranes / pathology
  • Intracellular Membranes / virology
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / metabolism*
  • Papillomavirus Infections / pathology
  • Proteolysis

Substances

  • Capsid Proteins
  • L2 protein, Human papillomavirus type 16
  • Molecular Chaperones
  • Oncogene Proteins, Viral
  • Amyloid Precursor Protein Secretases

Associated data

  • RefSeq/NM_000021
  • RefSeq/NG_007386