Suppressor of Cytokine Signaling 3 Is an Inducible Host Factor That Regulates Virus Egress during Ebola Virus Infection.

Abstract

UNLABELLED:

Ebola virus (EBOV) initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal EBOV infections. The VP40 matrix protein is a key viral structural protein that is critical for virion egress. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VP40-driven virus-like particles (VLPs) and infectious virus. Here, we show that host suppressor of cytokine signaling 3 (SOCS3) can also bind to EBOV VP40, leading to enhanced ubiquitinylation and egress of VP40. Indeed, titers of infectious EBOV derived from SOCS3 knockout mouse embryonic fibroblasts (MEFs) were significantly reduced compared to those from wild-type (WT) MEFs at 24 and 48 h postinfection. Importantly, this reduced virus yield could be rescued back to WT levels by exogenously expressing SOCS3. Lastly, we show that SOCS3 expression is induced by EBOV glycoprotein (GP) expression and that VLPs containing EBOV VP40 and GP induced production of proinflammatory cytokines, which induced SOCS3 for negative-feedback regulation. These data indicate that host innate immune protein SOCS3 may play an important role in budding and pathogenesis of EBOV.

IMPORTANCE:

The VP40 matrix protein is a key structural protein critical for Ebola virus budding. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VLPs and infectious virus. We reported that host TLR4 is a sensor for Ebola GP on VLPs and that the resultant TLR4 signaling pathways lead to the production of proinflammatory cytokines. Host SOCS3 regulates the innate immune response by controlling and limiting the proinflammatory response through negative-feedback inhibition of cytokine receptors. We present evidence that Ebola virus VLPs stimulate induction of SOCS3 as well as proinflammatory cytokines, and that expression of human SOCS3 enhances budding of Ebola VLPs and infectious virus via a mechanism linked to the host ubiquitinylation machinery.

• Authors: Atsushi Okumura, Angela L Rasmussen, Peter Halfmann, Friederike Feldmann, Akihiko Yoshimura, Heinz Feldmann, Yoshihiro Kawaoka, Ronald N Harty, Michael G Katze
• Journal: Journal of virology (J Virol) Vol. 89 Issue 20 Pg. 10399-406 (Oct 2015) ISSN: 1098-5514 [Electronic] United States
• PMID: 26246577 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• DNA-Binding Proteins
• Endosomal Sorting Complexes Required for Transport
• Glycoproteins
• Nucleoproteins
• SOCS3 protein, human
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• TLR4 protein, human
• Toll-Like Receptor 4
• Transcription Factors
• Tsg101 protein
• Viral Core Proteins
• nucleoprotein VP40, Ebola virus
• Nedd4 Ubiquitin Protein Ligases
• Nedd4 protein, human
• Nedd4l protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Animals
• Cell Line
• DNA-Binding Proteins (genetics, metabolism)
• Ebolavirus (genetics, metabolism)
• Endosomal Sorting Complexes Required for Transport (genetics, metabolism)
• Feedback, Physiological
• Fibroblasts (metabolism, virology)
• Gene Expression Regulation, Viral
• Glycoproteins (genetics, metabolism)
• HEK293 Cells
• Host-Pathogen Interactions
• Humans
• Macrophages (metabolism, virology)
• Mice
• Mice, Inbred C57BL
• Nedd4 Ubiquitin Protein Ligases
• Nucleoproteins (genetics, metabolism)
• Signal Transduction
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (genetics, metabolism)
• Toll-Like Receptor 4 (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination
• Viral Core Proteins (genetics, metabolism)
• Virion (genetics, metabolism)
• Virus Release (genetics)