A number of viruses exhibit bidirectional transport along microtubules following cell entry. Cytoplasmic dynein has been implicated in virus transport toward the nucleus, but the role of kinesins is poorly understood. They might either aid in virus infection, or serve in host defense. Adenovirus provides a simple model for addressing these questions and is the focus of this proposal. Prior studies from this lab worked out the mechanism for dynein recruitment to the adenovirus capsid, and identified roles for protein kinase A (PKA) in virus transport as well as in host cell defense.
The Aims of the proposed studies are 1) to identify kinesins involved in plus end-directed adenovirus transport during the early stages of infection;2) to determine the role of kinesins in host-adenovirus interactions;and 3) to test the effect of microtubule stabilization and posttranslational modifications on live adenovirus transport. The latter Aim will make use of high-resolution live adenovirus particle tracking analysis, and is designed to take advantage of and complement the Aims of other projects described in this Program Project application. The proposed investigation of adenovirus alone has important implications for understanding the cellular mechanisms involved in virus infection, identifying novel mechanisms for host cell defense, and improving the design of gene targeting vectors.

Public Health Relevance

Microtubule motor proteins are of wide importance in understanding many aspects of basic cell movement. Viruses use motor proteins during infection, and host cells for their own defense. This project investigates kinesin motor proteins in adenovirus infection, and has broad significance for understanding virus infectivity, host cell defense, and the design of advanced vectors for effective gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
1P01GM105536-01A1
Application #
8667738
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
Rosenfeld, Amy B; Doobin, David J; Warren, Audrey L et al. (2017) Replication of early and recent Zika virus isolates throughout mouse brain development. Proc Natl Acad Sci U S A 114:12273-12278
Naghavi, Mojgan H; Walsh, Derek (2017) Microtubule Regulation and Function during Virus Infection. J Virol 91:
Delaney, Michael Keegan; Malikov, Viacheslav; Chai, Qingqing et al. (2017) Distinct functions of diaphanous-related formins regulate HIV-1 uncoating and transport. Proc Natl Acad Sci U S A 114:E6932-E6941
Chai, Qingqing; Jovasevic, Vladimir; Malikov, Viacheslav et al. (2017) HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration. Nat Commun 8:1522
Malikov, Viacheslav; Naghavi, Mojgan H (2017) Localized Phosphorylation of a Kinesin-1 Adaptor by a Capsid-Associated Kinase Regulates HIV-1 Motility and Uncoating. Cell Rep 20:2792-2799
Bartolini, Francesca; Andres-Delgado, Laura; Qu, Xiaoyi et al. (2016) An mDia1-INF2 formin activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells. Mol Biol Cell 27:1797-808
Yi, Julie; Khobrekar, Noopur V; Dantas, Tiago J et al. (2016) Imaging of motor-dependent transport in neuronal and nonneuronal cells at high spatial and temporal resolution. Methods Cell Biol 131:453-65
Valle-Tenney, Roger; Opazo, Tatiana; Cancino, Jorge et al. (2016) Dynein Regulators Are Important for Ecotropic Murine Leukemia Virus Infection. J Virol 90:6896-905
Malikov, Viacheslav; da Silva, Eveline Santos; Jovasevic, Vladimir et al. (2015) HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus. Nat Commun 6:6660
Scherer, Julian; Vallee, Richard B (2015) Conformational changes in the adenovirus hexon subunit responsible for regulating cytoplasmic dynein recruitment. J Virol 89:1013-23

Showing the most recent 10 out of 11 publications