title: PLA2G16 represents a switch between entry and clearance of Picornaviridae.
abstract: Picornaviruses are a leading cause of human and veterinary infections that result in various diseases, including polio and the common cold. As archetypical non-enveloped viruses, their biology has been extensively studied. Although a range of different cell-surface receptors are bound by different picornaviruses, it is unclear whether common host factors are needed for them to reach the cytoplasm. Using genome-wide haploid genetic screens, here we identify the lipid-modifying enzyme PLA2G16 (refs 8, 9, 10, 11) as a picornavirus host factor that is required for a previously unknown event in the viral life cycle. We find that PLA2G16 functions early during infection, enabling virion-mediated genome delivery into the cytoplasm, but not in any virion-assigned step, such as cell binding, endosomal trafficking or pore formation. To resolve this paradox, we screened for suppressors of the ΔPLA2G16 phenotype and identified a mechanism previously implicated in the clearance of intracellular bacteria. The sensor of this mechanism, galectin-8 (encoded by LGALS8), detects permeated endosomes and marks them for autophagic degradation, whereas PLA2G16 facilitates viral genome translocation and prevents clearance. This study uncovers two competing processes triggered by virus entry: activation of a pore-activated clearance pathway and recruitment of a phospholipase to enable genome release.
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Staring
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Eleonore
authors.initials: E
authors.lastname: von Castelmur
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Blomen
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: van den Hengel
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Markus
authors.initials: M
authors.lastname: Brockmann
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors.forename: Jim
authors.initials: J
authors.lastname: Baggen
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Thibaut
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Joppe
authors.initials: J
authors.lastname: Nieuwenhuis
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: van Kuppeveld
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Carette
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.|Cancer GenomiCs.nl (CGC.nl), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
mesh_terms: D000818:Animals; D001343:Autophagy; D001692:Biological Transport; D002460:Cell Line; D003593:Cytoplasm / Q000235:genetics / Q000821:virology*; D011992:Endosomes / Q000378:metabolism; D005260:Female; D037161:Galectins / Q000235:genetics / Q000378:metabolism; D016679:Genome, Viral; D058605:Host-Derived Cellular Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010641:Phenotype; D054512:Phospholipases A2, Calcium-Independent / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010849:Picornaviridae / Q000235:genetics* / Q000502:physiology*; D013489:Suppression, Genetic; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D037161:Galectins; D058605:Host-Derived Cellular Factors; C091991:LGALS8 protein, human; D025521:Tumor Suppressor Proteins; C490065:PLAAT3 protein, human; D054512:Phospholipases A2, Calcium-Independent