Human Cytomegalovirus Directly Induces the Antiviral Protein Viperin to Enhance Infectivity

Seo, Jun-Young; Yaneva, Rakina; Hinson, Ella R.; Cresswell, Peter

doi:10.1126/science.1202007

Cited by 180 publications

(220 citation statements)

References 29 publications

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“…Interestingly, viperin, a protein causing actin disruption upon HCMV infection, has been reported to colocalize with vMIA to the mitochondria 1 d.p.i. and is redistributed to the AC at 3 d.p.i., 44 a timeframe coinciding with actin reorganization detected in our study. The observed reorganization of actin filaments at the area of the AC (Fig.…”

Section: Discussionmentioning

confidence: 78%

“…4a), shortly upon HCMV infection, actin fibers are disrupted and this has been reported to enhance the translocation of the incoming viral particles to the host nucleus and hence it is to the benefit of the virus. 44,46,59,60 However, the fate of actin cytoskeleton at late stages of the infection has not been thoroughly studied so far. To this end, HFFs were infected with wild-type HCMV and co-stained for the cytoplasmic protein, RhoB, as well as for actin using rhodamine-phalloidin.…”

Section: Depletion Of Rhob Results In Reduction Of Progeny Virion Promentioning

confidence: 99%

“…During the initial phase of HCMV infection, total and activated-RhoA levels are decreased and this contributes to the disruption of actin stress fibers, 43 a phenomenon that facilitates HCMV nuclear translocation. [44][45][46] HCMV-encoded chemokine receptor US-28 activates RhoA via Pyk2 mediating cellular motility and also activates b-catenin involving the Rho-Rho kinase (ROCK) pathway. 47,48 Moreover, the Rho GTPase CDC42 is miRNA-regulated and plays a role in HCMV AC morphogenesis along with RAB5C, RAB11A and SNAP23.…”

Section: Introductionmentioning

confidence: 99%

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RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

et al. 2015

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Human Cytomegalovirus (HCMV), an ubiquitous b-herpesvirus, is a significant pathogen that causes medically severe diseases in immunocompromised individuals and in congenitally infected neonates. RhoB belongs to the family of Rho GTPases, which regulates diverse cellular processes. Rho proteins are implicated in the entry and egress from the host cell of mainly a-and g-herpesviruses, whereas b-herpesviruses are the least studied in this regard. Here, we studied the role of RhoB GTPase during HCMV lytic infection. Microscopy analysis, both in fixed and live infected cells showed that RhoB was translocated to the assembly complex/compartment (AC) of HCMV, a cytoplasmic zone in infected cells where many viral structural proteins are known to accumulate and assembly of new virions takes place. Furthermore, RhoB was localized at the AC even when the expression of the late HCMV AC proteins was inhibited. At the very late stages of infection, cellular projections were formed containing RhoB and HCMV virions, potentially contributing to the successful viral spread. Interestingly, the knockdown of RhoB in HCMV-infected cells resulted in a significant reduction of the virus titer and could also affect the accumulation of AC viral proteins at this subcellular compartment. RhoB knockdown also affected actin fibers' structure. Actin reorganization was observed at late stages of infection originating from the viral AC and surrounding the cellular projections, implying a potential interplay between RhoB and actin during HCMV assembly and egress. In conclusion, our results demonstrate for the first time that RhoB is a constituent of the viral AC and is required for HCMV productive infection.

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Section: Discussionmentioning

confidence: 78%

Section: Depletion Of Rhob Results In Reduction Of Progeny Virion Promentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

et al. 2015

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“…The amphipathic α-helix domain mediates targeting of viperin to the cytosolic side of ER and lipid droplets (43,44) The central domain is homologous to the MoaA motif present in the family of radical S-adenosylmethionine (SAM) enzymes, which uses SAM as a cofactor to bind to proteins containing iron-sulfur clusters via the CxxxCxxC motif (45,46). Herein, we refer to the central domain as the radical SAM catalytic domain, and it has been demonstrated to inhibit virus replication (29,47). Even though the function of the C-terminal domain is poorly defined, it has been reported to play a role in inhibiting HCV replication (28).…”

Section: Viperin Inhibits Chikv Infection In Vitromentioning

confidence: 99%

Viperin restricts chikungunya virus replication and pathology

Teng¹,

Foo²,

Simamarta³

et al. 2012

J. Clin. Invest.

170

198

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Chikungunya virus (CHIKV) is a mosquito-borne arthralgia arbovirus that is reemergent in sub-Saharan Africa and Southeast Asia. CHIKV infection has been shown to be self-limiting, but the molecular mechanisms of the innate immune response that control CHIKV replication remain undefined. Here, longitudinal transcriptional analyses of PBMCs from a cohort of CHIKV-infected patients revealed that type I IFNs controlled CHIKV infection via RSAD2 (which encodes viperin), an enigmatic multifunctional IFN-stimulated gene (ISG). Viperin was highly induced in monocytes, the major target cell of CHIKV in blood. Anti-CHIKV functions of viperin were dependent on its localization in the ER, and the N-terminal amphipathic α-helical domain was crucial for its antiviral activity in controlling CHIKV replication. Furthermore, mice lacking Rsad2 had higher viremia and severe joint inflammation compared with wild-type mice. Our data demonstrate that viperin is a critical antiviral host protein that controls CHIKV infection and provide a preclinical basis for the design of effective control strategies against CHIKV and other reemerging arthrogenic alphaviruses.

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“…To do this, the PRRs RIG-I and MDA-5 recognize viral RNA in the cytosol and interact with an adapter on the mitochondrial membrane, MAVS, to trigger a signal transduction cascade that drives the production of IFN. IFN-g activates antiviral viperin (virus-inhibitory protein, ER-associated, IFN inducible) to translocate to mitochondria to reduce ATP generation (Seo et al 2011). Viperin is an iron-sulfur (Fe-S) clusterbinding antiviral protein that can be induced not only by IFN (types I and II) but also by LPS, dsRNA, and viral DNA.…”

Section: Mitochondrial Prolinflammatory Signals: the Inflammasomementioning

confidence: 99%

Ultrastructural Pathology and Interorganelle Cross Talk in Hepatotoxicity

Cheville

2013

Toxicol Pathol

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Mitochondria, endoplasmic reticulum (ER), cytoplasmic lipid droplets (CLD), and Golgi vesicles use cross talk to control hepatocyte metabolism, growth, and stress. Interpretation of ultrastructural change requires knowledge of how cross talk pathways function, how differential activation of hepatocellular signals influences organelle structure, and how organelles position themselves to become central hubs for stress responses. Mitochondria, by coupling energy production to pathways for protection, form critical platforms for innate signaling. Mitochondrial outer and inner membranes activate channels and signals to translocate peptides that drive oxidative phosphorylation, b-oxidation of fatty acids, and calcium ion (Ca 2þ ) flux. In cell stress, mitochondrial signals initiate fusion and fission, reactive oxygen species (ROS) control, autophagy, apoptosis, and senescence. Specialized tethering proteins tie mitochondria to ER to support translocation of metabolites. For Ca 2þ translocation, ER pores are connected to mitochondrial voltage-dependent anion channels, and for mitochondrial fission, unique membrane proteins pull ER to mitochondria. In toxic injury, cytosolic cytokines translocate to alter metabolism. Toxic effects on ER lipid synthesis lead to Golgi vesicle reduplication and transport of perilipin and other protein cargos into CLDs. How cellular proteostasis, oxidative homeostasis, and ion balance are maintained depend upon the effectiveness of mitochondrial ROS defense responses, unfolded protein responses in mitochondria and ER, and other organelle defenses.

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Human Cytomegalovirus Directly Induces the Antiviral Protein Viperin to Enhance Infectivity

Cited by 180 publications

References 29 publications

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

Viperin restricts chikungunya virus replication and pathology

Ultrastructural Pathology and Interorganelle Cross Talk in Hepatotoxicity

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