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Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress
- Source :
- PLoS Pathogens, Vol 13, Iss 1, p e1006132 (2017), PLOS Pathogens, PLoS Pathogens
- Publication Year :
- 2017
- Publisher :
- Public Library of Science (PLoS), 2017.
-
Abstract
- Ebola (EBOV) and Marburg (MARV) viruses are members of the Filoviridae family which cause outbreaks of hemorrhagic fever. The filovirus VP40 matrix protein is essential for virus assembly and budding, and its PPxY L-domain motif interacts with WW-domains of specific host proteins, such as Nedd4 and ITCH, to facilitate the late stage of virus-cell separation. To identify additional WW-domain-bearing host proteins that interact with VP40, we used an EBOV PPxY-containing peptide to screen an array of 115 mammalian WW-domain-bearing proteins. Using this unbiased approach, we identified BCL2 Associated Athanogene 3 (BAG3), a member of the BAG family of molecular chaperone proteins, as a specific VP40 PPxY interactor. Here, we demonstrate that the WW-domain of BAG3 interacts with the PPxY motif of both EBOV and MARV VP40 and, unexpectedly, inhibits budding of both eVP40 and mVP40 virus-like particles (VLPs), as well as infectious VSV-EBOV recombinants. BAG3 is a stress induced protein that regulates cellular protein homeostasis and cell survival through chaperone-mediated autophagy (CMA). Interestingly, our results show that BAG3 alters the intracellular localization of VP40 by sequestering VP40 away from the plasma membrane. As BAG3 is the first WW-domain interactor identified that negatively regulates budding of VP40 VLPs and infectious virus, we propose that the chaperone-mediated autophagy function of BAG3 represents a specific host defense strategy to counteract the function of VP40 in promoting efficient egress and spread of virus particles.<br />Author Summary The unprecedented magnitude and scope of the catastrophic 2014–2015 EBOV outbreak in West Africa, and its continued global emergence underscores the urgent need to better understand the biology and pathogenesis of this zoonotic pathogen. We have identified BAG3 as a novel and functional host VP40 interactor that negatively regulates VP40 VLP and virus egress in a PPxY/WW-domain dependent manner. As a cell survival protein and key regulator of chaperone-mediated autophagy (CMA), BAG3 sequesters EBOV and MARV VP40 away from the site of budding at the plasma membrane, and thus may represent a novel host defense strategy to combat filovirus VP40-mediated egress and spread.
- Subjects :
- 0301 basic medicine
Physiology
Protein Extraction
Nedd4 Ubiquitin Protein Ligases
viruses
Cell Membranes
Filoviridae
Pathogenesis
Pathology and Laboratory Medicine
medicine.disease_cause
Biochemistry
Chaperone-mediated autophagy
Cricetinae
Medicine and Health Sciences
Chemical Precipitation
Marburg Virus Disease
RNA, Small Interfering
lcsh:QH301-705.5
Virus Release
Extraction Techniques
biology
Chromatographic Techniques
Chemical Reactions
Hematology
Ebolavirus
Body Fluids
3. Good health
Transport protein
Cell biology
Chemistry
Protein Transport
Blood
Amino Acid Specific Chromatography
Host-Pathogen Interactions
Physical Sciences
RNA Interference
Anatomy
Cellular Structures and Organelles
Research Article
lcsh:Immunologic diseases. Allergy
Proline
Cell Survival
Ubiquitin-Protein Ligases
Immunology
Research and Analysis Methods
BAG3
Precipitates
Microbiology
Viral Matrix Proteins
03 medical and health sciences
VP40
Protein Domains
Cell Line, Tumor
Virology
Glutathione Chromatography
Autophagy
Genetics
medicine
Animals
Humans
Molecular Biology
Adaptor Proteins, Signal Transducing
Ebola virus
Endosomal Sorting Complexes Required for Transport
030102 biochemistry & molecular biology
Affinity Chromatography
Biology and Life Sciences
Membrane Proteins
Proteins
Correction
Cell Biology
Blood Serum
Hemorrhagic Fever, Ebola
biology.organism_classification
Marburgvirus
Protein Structure, Tertiary
Repressor Proteins
HEK293 Cells
030104 developmental biology
lcsh:Biology (General)
Parasitology
Apoptosis Regulatory Proteins
lcsh:RC581-607
Immune Serum
HeLa Cells
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 13
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....602ca5ae9891ffcf42921be25d85c7b4