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Article ; Online: Combating Intracellular Pathogens with Repurposed Host-Targeted Drugs.

Schor, Stanford / Einav, Shirit

ACS infectious diseases

2018 Volume 4, Issue 2, Page(s) 88–92

Abstract: There is a large, global unmet need for the development of countermeasures to combat intracellular pathogens. The development of novel antimicrobials is expensive and slow and typically focuses on selective inhibition of proteins encoded by a single ... ...

Abstract	There is a large, global unmet need for the development of countermeasures to combat intracellular pathogens. The development of novel antimicrobials is expensive and slow and typically focuses on selective inhibition of proteins encoded by a single pathogen, thereby providing a narrow spectrum of coverage. The repurposing of approved drugs targeting host functions required for microbial infections represents a promising alternative. This review summarizes progress and challenges in the repurposing of approved drugs as host-targeted broad-spectrum agents for the treatment of intracellular pathogens. These strategies include targeting both cellular factors required for infection by various viruses, intracellular bacteria, and/or protozoa as well as factors that modulate the host immune response to these microbial infections. The repurposed approach offers complementary means to develop therapeutics against existing and emerging intracellular microbial threats.
MeSH term(s)	Animals ; Anti-Infective Agents/pharmacology ; Antineoplastic Agents/pharmacology ; Drug Repositioning ; Humans ; Intracellular Space/drug effects ; Intracellular Space/microbiology ; Intracellular Space/virology ; Molecular Targeted Therapy
Chemical Substances	Anti-Infective Agents ; Antineoplastic Agents
Keywords	covid19
Language	English
Publishing date	2018-01-03
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.7b00268
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Repurposing of Kinase Inhibitors as Broad-Spectrum Antiviral Drugs.

Schor, Stanford / Einav, Shirit

DNA and cell biology

2017 Volume 37, Issue 2, Page(s) 63–69

Abstract: The high cost of drug development and the narrow spectrum of coverage typically provided by direct-acting antivirals limit the scalability of this antiviral approach. This review summarizes progress and challenges in the repurposing of approved kinase ... ...

Abstract	The high cost of drug development and the narrow spectrum of coverage typically provided by direct-acting antivirals limit the scalability of this antiviral approach. This review summarizes progress and challenges in the repurposing of approved kinase inhibitors as host-targeted broad-spectrum antiviral therapies.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Drug Repositioning ; Humans ; MAP Kinase Signaling System ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Virus Diseases/drug therapy ; Virus Diseases/enzymology
Chemical Substances	Antiviral Agents ; Protein Kinase Inhibitors
Keywords	covid19
Language	English
Publishing date	2017-11-17
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1024454-2
ISSN	1557-7430 ; 0198-0238 ; 1044-5498
ISSN (online)	1557-7430
ISSN	0198-0238 ; 1044-5498
DOI	10.1089/dna.2017.4033
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Article ; Online: Viral journeys on the intracellular highways.

Robinson, Makeda / Schor, Stanford / Barouch-Bentov, Rina / Einav, Shirit

Cellular and molecular life sciences : CMLS

2018 Volume 75, Issue 20, Page(s) 3693–3714

Abstract: Viruses are obligate intracellular pathogens that are dependent on cellular machineries for their replication. Recent technological breakthroughs have facilitated reliable identification of host factors required for viral infections and better ... ...

Abstract	Viruses are obligate intracellular pathogens that are dependent on cellular machineries for their replication. Recent technological breakthroughs have facilitated reliable identification of host factors required for viral infections and better characterization of the virus-host interplay. While these studies have revealed cellular machineries that are uniquely required by individual viruses, accumulating data also indicate the presence of broadly required mechanisms. Among these overlapping cellular functions are components of intracellular membrane trafficking pathways. Here, we review recent discoveries focused on how viruses exploit intracellular membrane trafficking pathways to promote various stages of their life cycle, with an emphasis on cellular factors that are usurped by a broad range of viruses. We describe broadly required components of the endocytic and secretory pathways, the Endosomal Sorting Complexes Required for Transport pathway, and the autophagy pathway. Identification of such overlapping host functions offers new opportunities to develop broad-spectrum host-targeted antiviral strategies.
MeSH term(s)	Autophagy ; Clathrin/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism ; Host-Pathogen Interactions ; Humans ; Intracellular Membranes/metabolism ; Intracellular Membranes/virology ; Lysosomes/metabolism ; Secretory Pathway ; Virus Internalization ; Viruses/metabolism ; Viruses/pathogenicity
Chemical Substances	Clathrin ; Endosomal Sorting Complexes Required for Transport
Keywords	covid19
Language	English
Publishing date	2018-07-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-018-2882-0
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Article ; Online: The cargo adapter protein CLINT1 is phosphorylated by the Numb-associated kinase BIKE and mediates dengue virus infection.

Schor, Stanford / Pu, Szuyuan / Nicolaescu, Vlad / Azari, Siavash / Kõivomägi, Mardo / Karim, Marwah / Cassonnet, Patricia / Saul, Sirle / Neveu, Gregory / Yueh, Andrew / Demeret, Caroline / Skotheim, Jan M / Jacob, Yves / Randall, Glenn / Einav, Shirit

The Journal of biological chemistry

2022 Volume 298, Issue 6, Page(s) 101956

Abstract: The signaling pathways and cellular functions regulated by the four Numb-associated kinases are largely unknown. We reported that AAK1 and GAK control intracellular trafficking of RNA viruses and revealed a requirement for BIKE in early and late stages ... ...

Abstract	The signaling pathways and cellular functions regulated by the four Numb-associated kinases are largely unknown. We reported that AAK1 and GAK control intracellular trafficking of RNA viruses and revealed a requirement for BIKE in early and late stages of dengue virus (DENV) infection. However, the downstream targets phosphorylated by BIKE have not yet been identified. Here, to identify BIKE substrates, we conducted a barcode fusion genetics-yeast two-hybrid screen and retrieved publicly available data generated via affinity-purification mass spectrometry. We subsequently validated 19 of 47 putative BIKE interactors using mammalian cell-based protein-protein interaction assays. We found that CLINT1, a cargo-specific adapter implicated in bidirectional Golgi-to-endosome trafficking, emerged as a predominant hit in both screens. Our experiments indicated that BIKE catalyzes phosphorylation of a threonine 294 CLINT1 residue both in vitro and in cell culture. Our findings revealed that CLINT1 phosphorylation mediates its binding to the DENV nonstructural 3 protein and subsequently promotes DENV assembly and egress. Additionally, using live-cell imaging we revealed that CLINT1 cotraffics with DENV particles and is involved in mediating BIKE's role in DENV infection. Finally, our data suggest that additional cellular BIKE interactors implicated in the host immune and stress responses and the ubiquitin proteasome system might also be candidate phosphorylation substrates of BIKE. In conclusion, these findings reveal cellular substrates and pathways regulated by the understudied Numb-associated kinase enzyme BIKE, a mechanism for CLINT1 regulation, and control of DENV infection via BIKE signaling, with potential implications for cell biology, virology, and host-targeted antiviral design.
MeSH term(s)	Animals ; Dengue/metabolism ; Dengue Virus/metabolism ; Humans ; Phosphorylation ; Two-Hybrid System Techniques ; Virus Replication
Language	English
Publishing date	2022-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.101956
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Article: Viral journeys on the intracellular highways

Robinson, Makeda / Schor, Stanford / Barouch-Bentov, Rina / Einav, Shirit

Cellular and molecular life sciences. 2018 Oct., v. 75, no. 20

2018

Abstract	Viruses are obligate intracellular pathogens that are dependent on cellular machineries for their replication. Recent technological breakthroughs have facilitated reliable identification of host factors required for viral infections and better characterization of the virus–host interplay. While these studies have revealed cellular machineries that are uniquely required by individual viruses, accumulating data also indicate the presence of broadly required mechanisms. Among these overlapping cellular functions are components of intracellular membrane trafficking pathways. Here, we review recent discoveries focused on how viruses exploit intracellular membrane trafficking pathways to promote various stages of their life cycle, with an emphasis on cellular factors that are usurped by a broad range of viruses. We describe broadly required components of the endocytic and secretory pathways, the Endosomal Sorting Complexes Required for Transport pathway, and the autophagy pathway. Identification of such overlapping host functions offers new opportunities to develop broad-spectrum host-targeted antiviral strategies.
Keywords	autophagy ; cell membranes ; highways ; pathogens ; physiological transport ; viruses ; covid19
Language	English
Dates of publication	2018-10
Size	p. 3693-3714.
Publishing place	Springer International Publishing
Document type	Article
Note	Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-018-2882-0
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Article ; Online: Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment.

Pu, Szu-Yuan / Xiao, Fei / Schor, Stanford / Bekerman, Elena / Zanini, Fabio / Barouch-Bentov, Rina / Nagamine, Claude M / Einav, Shirit

Antiviral research

2018 Volume 155, Page(s) 67–75

Abstract: There is an urgent need for strategies to combat dengue virus (DENV) infection; a major global threat. We reported that the cellular kinases AAK1 and GAK regulate intracellular trafficking of multiple viruses and that sunitinib and erlotinib, approved ... ...

Abstract	There is an urgent need for strategies to combat dengue virus (DENV) infection; a major global threat. We reported that the cellular kinases AAK1 and GAK regulate intracellular trafficking of multiple viruses and that sunitinib and erlotinib, approved anticancer drugs with potent activity against these kinases, protect DENV-infected mice from mortality. Nevertheless, further characterization of the therapeutic potential and underlying mechanism of this approach is required prior to clinical evaluation. Here, we demonstrate that sunitinib/erlotinib combination achieves sustained suppression of systemic infection at approved dose in DENV-infected IFN-α/β and IFN-γ receptor-deficient mice. Nevertheless, treatment with these blood-brain barrier impermeable drugs delays, yet does not prevent, late-onset paralysis; a common manifestation in this immunodeficient mouse model but not in humans. Sunitinib and erlotinib treatment also demonstrates efficacy in human primary monocyte-derived dendritic cells. Additionally, DENV infection induces expression of AAK1 transcripts, but not GAK, via single-cell transcriptomics, and these kinases are important molecular targets underlying the anti-DENV effect of sunitinib and erlotinib. Lastly, sunitinib/erlotinib combination alters inflammatory cytokine responses in DENV-infected mice. These findings support feasibility of repurposing sunitinib/erlotinib combination as a host-targeted antiviral approach and contribute to understanding its mechanism of antiviral action.
MeSH term(s)	Animals ; Antiviral Agents/therapeutic use ; Cells, Cultured ; Dendritic Cells/drug effects ; Dendritic Cells/virology ; Dengue/drug therapy ; Dengue Virus/drug effects ; Dengue Virus/physiology ; Drug Repositioning ; Erlotinib Hydrochloride/therapeutic use ; Feasibility Studies ; Female ; Gene Expression Profiling ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Protein Serine-Threonine Kinases/genetics ; Single-Cell Analysis ; Sunitinib/therapeutic use ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Erlotinib Hydrochloride (DA87705X9K) ; AAK1 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Sunitinib (V99T50803M)
Language	English
Publishing date	2018-05-16
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2018.05.001
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Article ; Online: BIKE regulates dengue virus infection and is a cellular target for broad-spectrum antivirals.

Pu, Szuyuan / Schor, Stanford / Karim, Marwah / Saul, Sirle / Robinson, Makeda / Kumar, Sathish / Prugar, Laura I / Dorosky, Danielle E / Brannan, Jennifer / Dye, John M / Einav, Shirit

Antiviral research

2020 Volume 184, Page(s) 104966

Abstract: Global health is threatened by emerging viruses, many of which lack approved therapies and effective vaccines, including dengue, Ebola, and Venezuelan equine encephalitis. We previously reported that AAK1 and GAK, two of the four members of the ... ...

Abstract	Global health is threatened by emerging viruses, many of which lack approved therapies and effective vaccines, including dengue, Ebola, and Venezuelan equine encephalitis. We previously reported that AAK1 and GAK, two of the four members of the understudied Numb-associated kinases (NAK) family, control intracellular trafficking of RNA viruses. Nevertheless, the role of BIKE and STK16 in viral infection remained unknown. Here, we reveal a requirement for BIKE, but not STK-16, in dengue virus (DENV) infection. BIKE mediates both early (postinternalization) and late (assembly/egress) stages in the DENV life cycle, and this effect is mediated in part by phosphorylation of a threonine 156 (T156) residue in the μ subunit of the adaptor protein (AP) 2 complex. Pharmacological compounds with potent anti-BIKE activity, including the investigational anticancer drug 5Z-7-oxozeaenol and more selective inhibitors, suppress DENV infection both in vitro and ex vivo. BIKE overexpression reverses the antiviral activity, validating that the mechanism of antiviral action is, at least in part, mediated by BIKE. Lastly, 5Z-7-oxozeaenol exhibits antiviral activity against viruses from three unrelated RNA viral families with a high genetic barrier to resistance. These findings reveal regulation of poorly understood stages of the DENV life cycle via BIKE signaling and establish a proof-of-principle that pharmacological inhibition of BIKE can be potentially used as a broad-spectrum strategy against acute emerging viral infections.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/antagonists & inhibitors ; Animals ; Antiviral Agents/pharmacology ; Cell Line ; Chlorocebus aethiops ; Dengue/drug therapy ; Dengue/virology ; Dengue Virus/drug effects ; Dengue Virus/physiology ; Drug Repositioning ; Host Microbial Interactions ; Humans ; Intracellular Signaling Peptides and Proteins/physiology ; Lactones/pharmacology ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/physiology ; RNA, Viral ; Recombinant Proteins ; Resorcinols/pharmacology ; Signal Transduction ; Transcription Factors/physiology ; Vero Cells ; Virus Internalization ; Virus Replication
Chemical Substances	7-oxozeanol ; AP2M1 protein, human ; Adaptor Proteins, Vesicular Transport ; Antiviral Agents ; Intracellular Signaling Peptides and Proteins ; Lactones ; Protein Kinase Inhibitors ; RNA, Viral ; Recombinant Proteins ; Resorcinols ; Transcription Factors ; AAK1 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; STK16 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2020-11-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2020.104966
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Article ; Online: MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment.

Kumar, Sathish / Barouch-Bentov, Rina / Xiao, Fei / Schor, Stanford / Pu, Szuyuan / Biquand, Elise / Lu, Albert / Lindenbach, Brett D / Jacob, Yves / Demeret, Caroline / Einav, Shirit

Cell reports

2019 Volume 26, Issue 7, Page(s) 1800–1814.e5

Abstract: The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) ...

Abstract	The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design.
MeSH term(s)	Cell Line, Tumor ; Endoplasmic Reticulum/metabolism ; HEK293 Cells ; Hepacivirus/metabolism ; Hepacivirus/pathogenicity ; Hepatitis C/genetics ; Hepatitis C/metabolism ; Hepatitis C/virology ; Humans ; Signal Transduction ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; Viral Nonstructural Proteins/metabolism
Chemical Substances	NS2 protein, Hepatitis C virus ; Ubiquitin ; Viral Nonstructural Proteins ; MARCHF8 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2019-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.01.075
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Article ; Online: Erratum for Barouch-Bentov et al., "Hepatitis C Virus Proteins Interact with the Endosomal Sorting Complex Required for Transport (ESCRT) Machinery via Ubiquitination To Facilitate Viral Envelopment".

Barouch-Bentov, Rina / Neveu, Gregory / Xiao, Fei / Beer, Melanie / Bekerman, Elena / Schor, Stanford / Campbell, Joseph / Boonyaratanakornkit, Jim / Lindenbach, Brett / Lu, Albert / Jacob, Yves / Einav, Shirit

mBio

2018 Volume 9, Issue 1

Language	English
Publishing date	2018-01-09
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.02234-17
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Article ; Online: Interactions between the Hepatitis C Virus Nonstructural 2 Protein and Host Adaptor Proteins 1 and 4 Orchestrate Virus Release.

Xiao, Fei / Wang, Stanley / Barouch-Bentov, Rina / Neveu, Gregory / Pu, Szuyuan / Beer, Melanie / Schor, Stanford / Kumar, Sathish / Nicolaescu, Vlad / Lindenbach, Brett D / Randall, Glenn / Einav, Shirit

mBio

2018 Volume 9, Issue 2

Abstract: Hepatitis C virus (HCV) spreads via secreted cell-free particles or direct cell-to-cell transmission. Yet, virus-host determinants governing differential intracellular trafficking of cell-free- and cell-to-cell-transmitted virus remain unknown. The host ... ...

Abstract	Hepatitis C virus (HCV) spreads via secreted cell-free particles or direct cell-to-cell transmission. Yet, virus-host determinants governing differential intracellular trafficking of cell-free- and cell-to-cell-transmitted virus remain unknown. The host adaptor proteins (APs) AP-1A, AP-1B, and AP-4 traffic in post-Golgi compartments, and the latter two are implicated in basolateral sorting. We reported that AP-1A mediates HCV trafficking during release, whereas the endocytic adaptor AP-2 mediates entry and assembly. We demonstrated that the host kinases AAK1 and GAK regulate HCV infection by controlling these clathrin-associated APs. Here, we sought to define the roles of AP-4, a clathrin-independent adaptor; AP-1A; and AP-1B in HCV infection. We screened for interactions between HCV proteins and the μ subunits of AP-1A, AP-1B, and AP-4 by mammalian cell-based protein fragment complementation assays. The nonstructural 2 (NS2) protein emerged as an interactor of these adaptors in this screening and by coimmunoprecipitations in HCV-infected cells. Two previously unrecognized dileucine-based motifs in the NS2 C terminus mediated AP binding and HCV release. Infectivity and coculture assays demonstrated that while all three adaptors mediate HCV release and cell-free spread, AP-1B and AP-4, but not AP-1A, mediate cell-to-cell spread. Live-cell imaging revealed HCV cotrafficking with AP-1A, AP-1B, and AP-4 and that AP-4 mediates HCV trafficking in a post-Golgi compartment. Lastly, HCV cell-to-cell spread was regulated by AAK1 and GAK and thus susceptible to treatment with AAK1 and GAK inhibitors. These data provide a mechanistic understanding of HCV trafficking in distinct release pathways and reveal a requirement for APs in cell-to-cell viral spread.
MeSH term(s)	Adaptor Protein Complex 1/metabolism ; Adaptor Protein Complex 4/metabolism ; Cell Line ; Hepacivirus/physiology ; Host-Pathogen Interactions ; Humans ; Immunoprecipitation ; Protein Binding ; Protein Interaction Mapping ; Viral Nonstructural Proteins/metabolism ; Virus Release
Chemical Substances	Adaptor Protein Complex 1 ; Adaptor Protein Complex 4 ; NS2 protein, Hepatitis C virus ; Viral Nonstructural Proteins
Language	English
Publishing date	2018-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.02233-17
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