GPR108 Is a Highly Conserved AAV Entry Factor.

Amino Acid Motifs Animals CRISPR-Cas Systems Capsid Proteins / chemistry Conserved Sequence Dependovirus / classification Evolution, Molecular Gene Transfer Techniques Genetic Engineering Genetic Therapy Genetic Vectors / genetics Genome, Viral Golgi Apparatus / metabolism Humans Phylogeny Protein Interaction Domains and Motifs
AAV CRISPR screen GPR108 adeno-associated virus endosomal escape entry in vivo receptor

Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
05 02 2020
Historique:
received: 04 04 2019
revised: 26 10 2019
accepted: 05 11 2019
pubmed: 1 12 2019
medline: 29 12 2020
entrez: 1 12 2019
Statut: ppublish

Résumé

Adeno-associated virus (AAV) is a highly promising gene transfer vector, yet major cellular requirements for AAV entry are poorly understood. Using a genome-wide CRISPR screen for entry of evolutionarily divergent serotype AAVrh32.33, we identified GPR108, a member of the G protein-coupled receptor superfamily, as an AAV entry factor. Of greater than 20 divergent AAVs across all AAV clades tested in human cell lines, only AAV5 transduction was unaffected in the GPR108 knockout (KO). GPR108 dependency was further shown in murine and primary cells in vitro. These findings are further validated in vivo, as the Gpr108 KO mouse demonstrates 10- to 100-fold reduced expression for AAV8 and rh32.33 but not AAV5. Mechanistically, both GPR108 N- and C-terminal domains are required for transduction, and on the capsid, a VP1 unique domain that is not conserved on AAV5 can be transferred to confer GPR108 independence onto AAV2 chimeras. In vitro binding and fractionation studies indicate reduced nuclear import and cytosolic accumulation in the absence of GPR108. We thus have identified the second of two AAV entry factors that is conserved between mice and humans relevant both in vitro and in vivo, further providing a mechanistic understanding to the tropism of AAV gene therapy vectors.

Identifiants

DOI: 10.1016/j.ymthe.2019.11.005 PMID: 31784416 PMC: PMC7000996
pubmed: 31784416
pii: S1525-0016(19)30501-5
doi: 10.1016/j.ymthe.2019.11.005
pmc: PMC7000996
pii:
doi:

Substances chimiques

Capsid Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

367-381

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI130123
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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Auteurs

Amanda M Dudek (AM)

Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass Eye and Ear, Boston, MA, USA; Ocular Genomics Institute, Mass Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Nerea Zabaleta (N)

Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass Eye and Ear, Boston, MA, USA; Ocular Genomics Institute, Mass Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Eric Zinn (E)

Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass Eye and Ear, Boston, MA, USA; Ocular Genomics Institute, Mass Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Sirika Pillay (S)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

James Zengel (J)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Caryn Porter (C)

Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.

Jennifer Santos Franceschini (JS)

Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass Eye and Ear, Boston, MA, USA; Ocular Genomics Institute, Mass Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Reynette Estelien (R)

Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass Eye and Ear, Boston, MA, USA; Ocular Genomics Institute, Mass Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Jan E Carette (JE)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Guo Ling Zhou (GL)

Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.

Luk H Vandenberghe (LH)

Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass Eye and Ear, Boston, MA, USA; Ocular Genomics Institute, Mass Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; The Broad Institute of Harvard and MIT, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address: luk_vandenberghe@meei.harvard.edu.

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Classifications MeSH

Recherchemedicale.com › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure secondaire des protéines › Motifs d'acides aminés › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Eucaryotes › Animaux › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Systèmes CRISPR-Cas › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales structurales › Protéines nucléocapside › Protéines de capside › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Phénomènes chimiques › Phénomènes biochimiques › Séquence conservée › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Virus › Virus à ADN › Parvoviridae › Parvovirinae › Dependovirus › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Phénomènes biologiques › Évolution biologique › Évolution moléculaire › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Techniques d'investigation › Techniques génétiques › Techniques de transfert de gènes › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Techniques d'investigation › Techniques génétiques › Génie génétique › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Techniques d'investigation › Techniques génétiques › Génie génétique › Thérapie génétique › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Phénomènes génétiques › Structures génétiques › Vecteurs génétiques › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Phénomènes génétiques › Structures génétiques › Génome › Génome microbien › Génome viral › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Appareil de Golgi › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Sciences de l'information › Phylogenèse › GPR108 Is a Highly Conserved AAV Entry Factor.
Recherchemedicale.com › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Motifs et domaines d'intéraction protéique › GPR108 Is a Highly Conserved AAV Entry Factor.