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Cell Rep. 2019 Feb 12;26(7):1800-1814.e5. doi: 10.1016/j.celrep.2019.01.075.

MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment.

Author information

1
Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
2
Département de Virologie, Unité de Génétique Moléculaire des Virus ARN (GMVR), Institut Pasteur, Centre National de la Recherche Scientifique; Université Paris Diderot, Paris, France.
3
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
4
Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT, USA.
5
Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: seinav@stanford.edu.

Abstract

The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design.

KEYWORDS:

ESCRT; HCV; MARCH8; assembly; envelopment; hepatitis C virus; intracellular membrane trafficking; proteomics; ubiquitination; virus-host interactions

PMID:
30759391
DOI:
10.1016/j.celrep.2019.01.075
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