Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R.

doi:10.1038/srep01813

Cited by 25 publications

(39 citation statements)

References 29 publications

(36 reference statements)

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“…Other groups have implicated APs in the life cycle of multiple unrelated viruses (17)(18)(19)(20)(21)(22)(23)(24)(25)(26), and we reported roles for AP2 in HCV entry and assembly (22,23). Our work demonstrated that through AP2 phosphorylation, AAK1 and GAK regulate these temporally distinct steps of the HCV life cycle, thereby, for the first time, uncovering their role as "master regulators" of a viral infection (22,23).…”

Section: Resultssupporting

confidence: 54%

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

Bekerman¹,

Neveu²,

Shulla³

et al. 2017

Journal of Clinical Investigation

212

309

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Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.

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Section: Resultssupporting

confidence: 54%

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

Bekerman¹,

Neveu²,

Shulla³

et al. 2017

Journal of Clinical Investigation

212

309

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show abstract

“…To achieve this, and to explore the possibility of CD2v contribution to Golgi and viral factory reorganization, we further characterized cellular markers of the TGN, potential candidates for interaction with the viral protein. One of the major players in Golgi organization is the AP-1 protein complex, which is involved in vesicle traffic between TGN and endosomes and is subverted by several viruses in order to modulate the infection [ 22 , 25 , 27 , 28 , 30 , 43 ]. Importantly, immune fluorescence assays showed that CD2v colocalized with AP-1 during ASFV-E70 infection in COS cells ( Fig 2A ) thus reinforcing a putative role for CD2v in Golgi reorganization during ASFV infection and in agreement with previous work showing ectopic CD2v in Golgi compartments [ 12 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…AP-1 has been shown to interact with several viral proteins including HIV-Nef and BPV-E6 [ 22 , 28 ]. The interaction between viral proteins and AP-1 has been proposed as a mechanism to subvert host cellular trafficking to ensure and optimize viral morphogenesis and viral egree while allowing immune evasion of the infected cell [ 25 , 27 , 28 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

CD2v Interacts with Adaptor Protein AP-1 during African Swine Fever Infection

et al. 2015

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African swine fever virus (ASFV) CD2v protein is believed to be involved in virulence enhancement, viral hemadsorption, and pathogenesis, although the molecular mechanisms of the function of this viral protein are still not fully understood. Here we describe that CD2v localized around viral factories during ASFV infection, suggesting a role in the generation and/or dynamics of these viral structures and hence in disturbing cellular traffic. We show that CD2v targeted the regulatory trans-Golgi network (TGN) protein complex AP-1, a key element in cellular traffic. This interaction was disrupted by brefeldin A even though the location of CD2v around the viral factory remained unchanged. CD2v-AP-1 binding was independent of CD2v glycosylation and occurred on the carboxy-terminal part of CD2v, where a canonical di-Leu motif previously reported to mediate AP-1 binding in eukaryotic cells, was identified. This motif was shown to be functionally interchangeable with the di-Leu motif present in HIV-Nef protein in an AP-1 binding assay. However, we demonstrated that it was not involved either in CD2v cellular distribution or in CD2v-AP-1 binding. Taken together, these findings shed light on CD2v function during ASFV infection by identifying AP-1 as a cellular factor targeted by CD2v and hence elucidate the cellular pathways used by the virus to enhance infectivity.

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“…Caco-2, A549, Huh-7, BHK-21, C6/36, HEp-2, PS, and MA104 cells were cultured as described previously (15)(16)(17). Virus strains used in the study and infection procedures has been described before (15)(16)(17). DENV-2 New Guinea C strain was a kind gift from Dr. Navin Khanna.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Most of the experiments have been performed in both the cell lines and we have obtained similar results. Plaque assay for DENV, JEV, and RV was set up in BHK-21, PS, and MA 104 cells respectively as described previously (15)(16)(17).…”

Section: Cells and Virusesmentioning

confidence: 99%

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

et al. 2019

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Zinc is an essential micronutrient which regulates diverse physiological functions and has been shown to play a crucial role in viral infections. Zinc has a necessary role in the replication of many viruses, however, antiviral action of zinc has also been demonstrated in in vitro infection models most likely through induction of host antiviral responses. Therefore, depending on the host machinery that the virus employs at different stages of infection, zinc may either facilitate, or inhibit virus infection. In this study, we show that zinc plays divergent roles in rotavirus and dengue virus infections in epithelial cells. Dengue virus infection did not perturb the epithelial barrier functions despite the release of virus from the basolateral surface whereas rotavirus infection led to disruption of epithelial junctions. In rotavirus infection, zinc supplementation post-infection did not block barrier disruption suggesting that zinc does not affect rotavirus life-cycle or protects epithelial barriers post-infection suggesting the involvement of cellular pathways in the beneficial effect of zinc supplementation in enteric infections. Zinc depletion by N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) inhibited dengue virus and Japanese encephalitis virus (JEV) infection but had no effect on rotavirus. Time-of-addition experiments suggested that zinc chelation affected both early and late stages of dengue virus infectious cycle and zinc chelation abrogated dengue virus RNA replication. We show that transient zinc chelation induces ER stress and antiviral response by activating NF-kappaB leading to induction of interferon signaling. These results suggest that modulation of zinc homeostasis during virus infection could be a component of host antiviral response and altering zinc homeostasis may act as a potent antiviral strategy against flaviviruses.

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Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle

Cited by 25 publications

References 29 publications

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

CD2v Interacts with Adaptor Protein AP-1 during African Swine Fever Infection

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

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