ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication
| Autor: | Margaret R. MacDonald, Melody M. H. Li, Charles M. Rice, Lok Man J. Law, Shihyun You, Andrea Jurado, Brandon S. Razooky |
|---|---|
| Přispěvatelé: | Randall, Glenn |
| Rok vydání: | 2019 |
| Předmět: |
RNA viruses
Messenger Gene Expression Virus Replication Biochemistry Virions Diagnostic Radiology BHK cells RNA interference Medicine and Health Sciences Tumor Cells Cultured Replicon Amino Acids Biology (General) Cellular Stress Responses Osteosarcoma 0303 health sciences Alanine Cultured biology Organic Compounds Radiology and Imaging 030302 biochemistry & molecular biology Infection Imaging RNA-Binding Proteins hemic and immune systems Transfection Tumor Cells 3. Good health Cell biology Chemistry Protein Transport Infectious Diseases Cell Processes Medical Microbiology Viruses Physical Sciences Cell lines RNA Interference Biological cultures Infection Research Article Sindbis virus Imaging Techniques QH301-705.5 Physiological Immunology Antiviral protein Bone Neoplasms chemical and pharmacologic phenomena Viral Structure Research and Analysis Methods Cytoplasmic Granules Stress Antiviral Agents Microbiology Virus Vaccine Related 03 medical and health sciences Stress granule stomatognathic system Diagnostic Medicine Stress Physiological Biodefense Virology Genetics Humans RNA Messenger Molecular Biology 030304 developmental biology Alphavirus Infections Prevention Organic Chemistry Organisms Chemical Compounds Biology and Life Sciences Proteins Cell Biology RC581-607 biology.organism_classification Viral Replication Vector-Borne Diseases Emerging Infectious Diseases Aliphatic Amino Acids Viral replication RNA Protein Translation Parasitology Sindbis Virus Immunologic diseases. Allergy |
| Zdroj: | PLoS pathogens, vol 15, iss 5 PLoS Pathogens, Vol 15, Iss 5, p e1007798 (2019) PLoS Pathogens |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1007798 |
| Popis: | Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP’s antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP’s localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP’s ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread. Author summary Organisms encode immune programs, present in most somatic cells, to combat pathogens. The components of these antiviral programs are both constitutively expressed and highly upregulated upon pathogen recognition. Interestingly, a broadly acting antiviral factor is the zinc-finger antiviral protein (ZAP). ZAP is a primarily cytoplasmic protein that upon various cellular stresses, such as virus infection, can localize to specific cytoplasmic complexes termed stress granules (SGs). SGs are hubs that regulate mRNA stability and translation. Here, we show that SG localization is (i) correlated with ZAP’s antiviral function, (ii) most likely triggered during the early stages of virus replication, and (iii) a highly dynamic and transient process. Collectively, our data highlight the genetic and dynamic components of ZAP-mediated antiviral activity. |
| Databáze: | OpenAIRE |
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