Abstract
Intracellular transport of cargos, including many viruses, involves directed movement on microtubules mediated by motor proteins. While a number of viruses bind motors of opposing directionality, how they associate with and control these motors to accomplish directed movement remains poorly understood. Here we show that human immunodeficiency virus type 1 (HIV-1) associates with the kinesin-1 adaptor protein, Fasiculation and Elongation Factor zeta 1 (FEZ1). RNAi-mediated FEZ1 depletion blocks early infection, with virus particles exhibiting bidirectional motility but no net movement to the nucleus. Furthermore, both dynein and kinesin-1 motors are required for HIV-1 trafficking to the nucleus. Finally, the ability of exogenously expressed FEZ1 to promote early HIV-1 infection requires binding to kinesin-1. Our findings demonstrate that opposing motors both contribute to early HIV-1 movement and identify the kinesin-1 adaptor, FEZ1 as a capsid-associated host regulator of this process usurped by HIV-1 to accomplish net inward movement toward the nucleus.
Highlights
Intracellular transport of cargos, including many viruses, involves directed movement on microtubules mediated by motor proteins
To test if endogenous fasciculation and elongation protein zeta-1 (FEZ1) levels in non-neuronal cells could influence their susceptibility to infection, FEZ1 was depleted in normal human dermal fibroblasts (NHDFs), microglia (CHME3) or macrophages using RNA interference
Small interfering RNA-treated cells were infected with human immunodeficiency virus type 1 (HIV-1) carrying a luciferase reporter gene and pseudotyped with vesicular stomatitis virus G (VSV-G) envelope glycoprotein, widely used to improve HIV-1 infectivity and which mediates endocytic fusion, one of the entry pathways used by HIV-1
Summary
Intracellular transport of cargos, including many viruses, involves directed movement on microtubules mediated by motor proteins. RNAi-mediated FEZ1 depletion blocks early infection, with virus particles exhibiting bi-directional motility but no net movement to the nucleus Both dynein and kinesin-1 motors are required for HIV-1 trafficking to the nucleus. Our findings demonstrate that opposing motors both contribute to early HIV-1 movement and identify the kinesin-1 adaptor, FEZ1 as a capsid-associated host regulator of this process usurped by HIV-1 to accomplish net inward movement towards the nucleus. Our findings suggest that FEZ1 does not affect specific HIV-1 nuclear entry pathways but, instead, HIV-1 capsids bind FEZ1, a kinesin-1 adaptor protein, to regulate viral movement towards the nucleus. Our findings suggest that opposing motors contribute to bi-directional HIV-1 movement, and that incoming viral particles usurp the kinesinadaptor function of the host protein, FEZ1, to regulate this process and accomplish net retrograde movement to the nucleus
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