title: Co-option of Membrane Wounding Enables Virus Penetration into Cells.
abstract: During cell entry, non-enveloped viruses undergo partial uncoating to expose membrane lytic proteins for gaining access to the cytoplasm. We report that adenovirus uses membrane piercing to induce and hijack cellular wound removal processes that facilitate further membrane disruption and infection. Incoming adenovirus stimulates calcium influx and lysosomal exocytosis, a membrane repair mechanism resulting in release of acid sphingomyelinase (ASMase) and degradation of sphingomyelin to ceramide lipids in the plasma membrane. Lysosomal exocytosis is triggered by small plasma membrane lesions induced by the viral membrane lytic protein-VI, which is exposed upon mechanical cues from virus receptors, followed by virus endocytosis into leaky endosomes. Chemical inhibition or RNA interference of ASMase slows virus endocytosis, inhibits virus escape to the cytosol, and reduces infection. Ceramide enhances binding of protein-VI to lipid membranes and protein-VI-induced membrane rupture. Thus, adenovirus uses a positive feedback loop between virus uncoating and lipid signaling for efficient membrane penetration.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Molecular Life Sciences Graduate School, ETH and University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Stefania
authors.initials: S
authors.lastname: Luisoni
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Suomalainen
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Karin
authors.initials: K
authors.lastname: Boucke
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
authors.forename: Lukas B
authors.initials: LB
authors.lastname: Tanner
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, and University of Basel, 4000 Basel, Switzerland.
authors.forename: Xue Li
authors.initials: XL
authors.lastname: Guan
authors.affiliation: Paul Langerhans Institute Dresden of the Helmholtz Centre Munich at the University Clinic Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany.
authors.forename: Michał
authors.initials: M
authors.lastname: Grzybek
authors.affiliation: Paul Langerhans Institute Dresden of the Helmholtz Centre Munich at the University Clinic Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany.
authors.forename: Ünal
authors.initials: Ü
authors.lastname: Coskun
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: urs.greber@imls.uzh.ch.
authors.forename: Urs F
authors.initials: UF
authors.lastname: Greber
mesh_terms: D000256:Adenoviridae / Q000201:enzymology / Q000502:physiology*; D001711:Biotransformation; D036022:Capsid Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology*; D002518:Ceramides / Q000378:metabolism; D004705:Endocytosis; D005089:Exocytosis; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D036022:Capsid Proteins; D002518:Ceramides; D013109:Sphingomyelins; C090876:polypeptide VI, adenovirus; D013108:Sphingomyelin Phosphodiesterase