Marburg virus exploits the Rab11-mediated endocytic pathway in viral-particle production

Author:

Furuyama Wakako1ORCID,Yamada Kento1,Sakaguchi Miako2ORCID,Marzi Andrea3ORCID,Nanbo Asuka1ORCID

Affiliation:

1. National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki, Japan

2. Central Laboratory, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan

3. Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA

Abstract

ABSTRACT Filoviruses produce viral particles with characteristic filamentous morphology. The major viral matrix protein, VP40, is trafficked to the plasma membrane and promotes viral particle formation and subsequent viral egress. In the present study, we assessed the role of the small GTPase Rab11-mediated endocytic pathway in Marburg virus (MARV) particle formation and budding. Although Rab11 was predominantly localized in the perinuclear region, it exhibited a more diffuse distribution in the cytoplasm of cells transiently expressing MARV VP40. Rab11 was incorporated into MARV-like particles. Expression of the dominant-negative form of Rab11 and knockdown of Rab11 decreased the amount of VP40 fractions in the cell periphery. Moreover, downregulation of Rab11 moderately reduced the release of MARV-like particles and authentic MARV. We further demonstrated that VP40 induces the distribution of the microtubule network toward the cell periphery, which was partly associated with Rab11. Depolymerization of microtubules reduced the accumulation of VP40 in the cell periphery along with viral particle formation. VP40 physically interacted with α-tubulin, a major component of microtubules, but not with Rab11. Taken together, these results suggested that VP40 partly interacts with microtubules and facilitates their distribution toward the cell periphery, leading to the trafficking of transiently tethering Rab11-positive vesicles toward the cell surface. As we previously demonstrated the role of Rab11 in the formation of Ebola virus particles, the results here suggest that filoviruses in general exploit the vesicle-trafficking machinery for proper virus-particle formation and subsequent egress. These pathways may be a potential target for the development of pan-filovirus therapeutics. IMPORTANCE Filoviruses, including Marburg and Ebola viruses, produce distinct filamentous viral particles. Although it is well known that the major viral matrix protein of these viruses, VP40, is trafficked to the cell surface and promotes viral particle production, details regarding the associated molecular mechanisms remain unclear. To address this knowledge gap, we investigated the role of the small GTPase Rab11-mediated endocytic pathway in this process. Our findings revealed that Marburg virus exploits the Rab11-mediated vesicle-trafficking pathway for the release of virus-like particles and authentic virions in a microtubule network-dependent manner. Previous findings demonstrated that Rab11 is also involved in Ebola virus-particle production. Taken together, these data suggest that filoviruses, in general, may hijack the microtubule-dependent vesicle-trafficking machinery for productive replication. Therefore, this pathway presents as a potential target for the development of pan-filovirus therapeutics.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

MEXT | Japan Science and Technology Agency

Takeda Medical Research Foundation

Daiichi Sankyo Foundation of Life Science

Hayashi Memorial Foundation for Female Natural Scientists

Mochida Memorial Foundation for Medical and Pharmaceutical Research

Chugai Foundation for Innovative Drug Discovery Science

Suhara Memorial Foundation

Akiyama Life Science Foundation

HHS | NIH | NIAID | Division of Intramural Research

Publisher

American Society for Microbiology

Reference70 articles.

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5. Feldmann H, Sanchez A, Geisbert T. 2013. Filoviridae: Marburg and Ebola viruses. In Knipe M, Howley PM (ed), Fields virology, 6th ed. Lippincott Williams & Wilkins, Philadelphia, PA.

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