Dataset Information

Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo.

ABSTRACT: Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbp transport is regulated. From a forward genetic screen for myelination defects in zebrafish, we identified a mutation in actr10, which encodes the Arp11 subunit of dynactin, a critical activator of the retrograde motor dynein. Both the actr10 mutation and pharmacological dynein inhibition in zebrafish result in failure to properly distribute mbp mRNA in oligodendrocytes, indicating a paradoxical role for the retrograde dynein/dynactin complex in anterograde mbp mRNA transport. To address the molecular mechanism underlying this observation, we biochemically isolated reporter-tagged Mbp mRNA granules from primary cultured mammalian oligodendrocytes to show that they indeed associate with the retrograde motor complex. Next, we used live-cell imaging to show that acute pharmacological dynein inhibition quickly arrests Mbp mRNA transport in both directions. Chronic pharmacological dynein inhibition also abrogates Mbp mRNA distribution and dramatically decreases MBP protein levels. Thus, these cell culture and whole animal studies demonstrate a role for the retrograde dynein/dynactin motor complex in anterograde mbp mRNA transport and myelination in vivo.

SUBMITTER: Herbert AL

PROVIDER: S-EPMC5664533 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo.

Herbert Amy L AL Fu Meng-Meng MM Drerup Catherine M CM Gray Ryan S RS Harty Breanne L BL Ackerman Sarah D SD O'Reilly-Pol Thomas T Johnson Stephen L SL Nechiporuk Alex V AV Barres Ben A BA Monk Kelly R KR

Proceedings of the National Academy of Sciences of the United States of America 20171012 43

Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbp tra ...[more]

PMID: 29073112

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Project description:Human immunodeficiency virus type 1 (HIV-1) infection depends on efficient intracytoplasmic transport of the incoming viral core to the target cell nucleus. Evidence suggests that this movement is facilitated by the microtubule motor dynein, a large multiprotein complex that interacts with dynactin and cargo-specific adaptor proteins for retrograde movement via microtubules. Dynein adaptor proteins are necessary for activating dynein movement and for linking specific cargoes to dynein. We hypothesized that HIV-1 engages the dynein motor complex via an adaptor for intracellular transport. Here, we show that small interfering RNA depletion of the dynein heavy chain, components of the dynactin complex, and the dynein adaptor BICD2 reduced cell permissiveness to HIV-1 infection. Cell depletion of dynein heavy chain and BICD2 resulted in impaired HIV-1 DNA accumulation in the nucleus and decreased retrograde movement of the virus. Biochemical studies revealed that dynein components and BICD2 associate with capsid-like assemblies of the HIV-1 CA protein in cell extracts and that purified recombinant BICD2 binds to CA assemblies in vitro Association of dynein with CA assemblies was reduced upon immunodepletion of BICD2 from cell extracts. We conclude that BICD2 is a capsid-associated dynein adaptor utilized by HIV-1 for transport to the nucleus.IMPORTANCE During HIV-1 infection, the virus must travel across the cytoplasm to enter the nucleus. The host cell motor protein complex dynein has been implicated in HIV-1 intracellular transport. We show that expression of the dynein heavy chain, components of the dynein-associated dynactin complex, and the dynein adaptor BICD2 in target cells are important for HIV-1 infection and nuclear entry. BICD2 interacts with the HIV-1 capsid in vitro, suggesting that it functions as a capsid-specific adaptor for HIV-1 intracellular transport. Our work identifies specific host proteins involved in microtubule-dependent HIV-1 intracellular transport and highlights the BICD2-capsid interaction as a potential target for antiviral therapy.

Dataset Information

Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo.

Publications

Dynein/dynactin is necessary for anterograde transport of <i>Mbp</i> mRNA in oligodendrocytes and for myelination in vivo.

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