Interferon-induced transmembrane protein 3 blocks fusion of sensitive but not resistant viruses by partitioning into virus-carrying endosomes.
A549 Cells
/ metabolism
Animals
Antiviral Agents
/ metabolism
COS Cells
/ metabolism
Chlorocebus aethiops
Endosomes
/ metabolism
HEK293 Cells
/ metabolism
Host-Pathogen Interactions
Humans
Influenza A virus
/ pathogenicity
Interferons
/ metabolism
Lassa virus
/ pathogenicity
Membrane Proteins
/ metabolism
Optical Imaging
/ methods
Protein Transport
RNA-Binding Proteins
/ metabolism
Virus Internalization
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
12
09
2018
accepted:
14
12
2018
revised:
25
01
2019
pubmed:
15
1
2019
medline:
19
3
2019
entrez:
15
1
2019
Statut:
epublish
Résumé
Late endosome-resident interferon-induced transmembrane protein 3 (IFITM3) inhibits fusion of diverse viruses, including Influenza A virus (IAV), by a poorly understood mechanism. Despite the broad antiviral activity of IFITM3, viruses like Lassa virus (LASV), are fully resistant to its inhibitory effects. It is currently unclear whether resistance arises from a highly efficient fusion machinery that is capable of overcoming IFITM3 restriction or the ability to enter from cellular sites devoid of this factor. Here, we constructed and validated a functional IFITM3 tagged with EGFP or other fluorescent proteins. This breakthrough allowed live cell imaging of virus co-trafficking and fusion with endosomal compartments in cells expressing fluorescent IFITM3. Three-color single virus and endosome tracking revealed that sensitive (IAV), but not resistant (LASV), viruses become trapped within IFITM3-positive endosomes where they underwent hemifusion but failed to release their content into the cytoplasm. IAV fusion with IFITM3-containing compartments could be rescued by amphotericin B treatment, which has been previously shown to antagonize the antiviral activity of this protein. By comparison, virtually all LASV particles trafficked and fused with endosomes lacking detectable levels of fluorescent IFITM3, implying that this virus escapes restriction by utilizing endocytic pathways that are distinct from the IAV entry pathways. The importance of virus uptake and transport pathways is further reinforced by the observation that LASV glycoprotein-mediated cell-cell fusion is inhibited by IFITM3 and other members of the IFITM family expressed in target cells. Together, our results strongly support a model according to which IFITM3 accumulation at the sites of virus fusion is a prerequisite for its antiviral activity and that this protein traps viral fusion at a hemifusion stage by preventing the formation of fusion pores. We conclude that the ability to utilize alternative endocytic pathways for entry confers IFITM3-resistance to otherwise sensitive viruses.
Identifiants
pubmed: 30640957
doi: 10.1371/journal.ppat.1007532
pii: PPATHOGENS-D-18-01791
pmc: PMC6347298
doi:
Substances chimiques
Antiviral Agents
0
IFITM3 protein, human
0
Membrane Proteins
0
RNA-Binding Proteins
0
Interferons
9008-11-1
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
e1007532Subventions
Organisme : NIAID NIH HHS
ID : R01 AI053668
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI135806
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM054787
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM101539
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist
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