HIV‐1 integrase trafficking in <i>S. cerevisiae</i>: a useful model to dissect the microtubule network involvement of viral protein nuclear import

Desfarges, Sébastien; Salin, Bénédicte; Calmels, Christina; Andréola, Marie-Line; Parissi, Vincent; Fournier, Michel

doi:10.1002/yea.1651

Cited by 24 publications

(22 citation statements)

References 53 publications

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“…We showed that NLS-mediated and dynein-mediated pathways act redundantly to ensure normal METT-10 nuclear accumulation. The role of dynein and the microtubule network, and specifically LC8-type light chains, in facilitating the nuclear import of proteins is well documented (11,16,37,48,54,57). However, in cases where it has been examined, dynein mediates nuclear accumulation by enhancing the efficiency of NLS-dependent nuclear import (37,48).…”

Section: Discussionmentioning

confidence: 99%

A Role for Dynein in the Inhibition of Germ Cell Proliferative Fate

Dorsett

Schedl

2009

Molecular and Cellular Biology

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During normal development as well as in diseased states such as cancer, extracellular "niches" often provide cues to proximal cells and activate intracellular pathways. Activation of such signaling pathways in turn instructs cellular proliferation and differentiation. In the Caenorhabditis elegans gonad, GLP-1/Notch signaling instructs germ line stem cells to self-renew through mitotic cell division. As germ cells progressively move out of the niche, they differentiate by entering meiosis and eventually form gametes. In this model system, we uncovered an unexpected role for the dynein motor complex in promoting normal differentiation of proliferating germ cells. We demonstrate that dynein light chain 1 (DLC-1) and its partner, dynein heavy chain 1, inhibit the proliferative cell fate, in part through regulation of METT-10, a conserved putative methyltransferase. We show that DLC-1 physically interacts with METT-10 and promotes both its overall levels and nuclear accumulation. Our results add a new dimension to the processes controlled by the dynein motor complex, demonstrating that dynein can act as an antiproliferative factor.

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Section: Discussionmentioning

confidence: 99%

A Role for Dynein in the Inhibition of Germ Cell Proliferative Fate

Dorsett

Schedl

2009

Molecular and Cellular Biology

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“…Identifying the host proteins required for retrovirus infection has been a major challenge. Many screens have been performed for this purpose, including yeast two-hybrid screens of cDNA expression libraries with viral proteins as bait (5)(6)(7)(8), biochemical screens of host proteins copurifying with viral proteins (9), and functional screens of cDNA overexpression libraries (10,11) or knockdown libraries based on small interfering RNAs for those members that affect infection (12)(13)(14). In the case of the murine leukemia viruses (MLVs), most such screens have been performed with isolated viral proteins or expressed viral genes and not in the context of replicating virus or the complete preintegration complex (PIC).…”

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confidence: 99%

Dynein Regulators Are Important for Ecotropic Murine Leukemia Virus Infection

Valle-Tenney

Opazo

Cancino

et al. 2016

J Virol

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During the early steps of infection, retroviruses must direct the movement of the viral genome into the nucleus to complete their replication cycle. This process is mediated by cellular proteins that interact first with the reverse transcription complex and later with the preintegration complex (PIC), allowing it to reach and enter the nucleus. For simple retroviruses, such as murine leukemia virus (MLV), the identities of the cellular proteins involved in trafficking of the PIC in infection are unknown. To identify cellular proteins that interact with the MLV PIC, we developed a replication-competent MLV in which the integrase protein was tagged with a FLAG epitope. Using a combination of immunoprecipitation and mass spectrometry, we established that the microtubule motor dynein regulator DCTN2/p50/dynamitin interacts with the MLV preintegration complex early in infection, suggesting a direct interaction between the incoming viral particles and the dynein complex regulators. Further experiments showed that RNA interference (RNAi)-mediated silencing of either DCTN2/p50/dynamitin or another dynein regulator, NudEL, profoundly reduced the efficiency of infection by ecotropic, but not amphotropic, MLV reporters. We propose that the cytoplasmic dynein regulators are a critical component of the host machinery needed for infection by the retroviruses entering the cell via the ecotropic envelope pathway. IMPORTANCERetroviruses must access the chromatin of host cells to integrate the viral DNA, but before this crucial event, they must reach the nucleus. The movement through the cytoplasm-a crowded environment where diffusion is slow-is thought to utilize retrograde transport along the microtubule network by the dynein complex. Different viruses use different components of this multisubunit complex. We found that the preintegration complex of murine leukemia virus (MLV) interacts with the dynein complex and that regulators of this complex are essential for infection. Our study provides the first insight into the requirements for retrograde transport of the MLV preintegration complex.

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“…DYNLL or LC8 has been involved in foamy virus association with centrosomes, mediated by a direct interaction between Gag and DYNLL (13). By use of a Saccharomyces cerevisiae model, it has been shown that HIV-1 IN associates with Dyn2p, a DYNLL ortholog (21), and a functional interaction between DYNLL1 and HIV-1 has also been demonstrated (9). In the case of BIV, DYNLL interacts directly with the CA proteins, and this interaction mediates retrograde transport of the incoming virus (15).…”

Section: Discussionmentioning

confidence: 99%

“…The intermediate chain mediates not only cargo association with the dynein complex but also the association of the light-intermediate and light chains with the heavy chain. Some retroviruses, such as bovine immunodeficiency virus (BIV), Mason-Pfizer monkey virus (MPMV), prototype foamy virus (PFV), and human immunodeficiency virus type 1 (HIV-1), interact directly with the cytoplasmic dynein light chains for their retrograde transport (13,15,(19)(20)(21). Thus, the association of retroviruses with dynein light chains seems to be a common mechanism.…”

mentioning

confidence: 99%

Functional Evidence of the Involvement of the Dynein Light Chain DYNLRB2 in Murine Leukemia Virus Infection

Opazo

Garcés

Tapia

et al. 2017

J Virol

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How murine leukemia virus (MLV) travels from the cell membrane to the nucleus and the mechanism for nuclear entry of MLV DNA in dividing cells still remain unclear. It seems likely that the MLV preintegration complex (PIC) interacts with cellular proteins to perform these tasks. We recently published that the microtubule motor cytoplasmic dynein complex and its regulator proteins interact with the MLV PIC at early times of infection, suggesting a functional interaction between the incoming viral particles, the dynein complex, and dynein regulators. To better understand the role of the dynein complex in MLV infection, we performed short hairpin RNA (shRNA) screening of the dynein light chains on MLV infection. We found that silencing of a specific light chain of the cytoplasmic dynein complex, DYNLRB2, reduced the efficiency of infection by MLV reporter viruses without affecting HIV-1 infection. Furthermore, the overexpression of DYNLRB2 increased infection by MLV. We conclude that the DYNLRB2 light chain of the cytoplasmic dynein complex is an important and specific piece of the host machinery needed for MLV infection.IMPORTANCE Retroviruses must reach the chromatin of their host to integrate their viral DNA, but first they must get into the nucleus. The cytoplasm is a crowded environment in which simple diffusion is slow, and thus viruses utilize retrograde transport along the microtubule network, mediated by the dynein complex. Different viruses use different components of this multisubunit complex. We have found that murine leukemia virus (MLV) associates functionally and specifically with the dynein light chain DYNLRB2, which is required for infection. Our study provides more insight into the molecular requirements for retrograde transport of the MLV preintegration complex and demonstrates, for the first time, a role for DYNLRB2 in viral infection. KEYWORDS MLV, dynein, dynein light chain, DYNLRB2D uring early steps of infection, retroviruses must reach the nucleus, cross the nuclear membrane, and access the host cell genome. The cytoplasm is extremely crowded, and simple diffusion is predicted to be too slow to explain the kinetics of virus infection (1). Many retroviruses are actively transported along microtubules (2-4) to move through the cytoplasm and reach the nucleus, and the microtubule retrograde transport complex dynein has been shown to have an important role in trafficking and infection for several viral families (2,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).Murine leukemia virus (MLV) belongs to the Gammaretrovirus genus, whose members are strongly dependent on cell division to gain entry into the nucleus. These viruses do not have the ability to cross the nuclear membrane of nondividing cells and rather must wait for nuclear membrane breakdown to occur during mitosis to access host chromatin. Several screens have revealed that cytoskeleton-associated proteins

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HIV‐1 integrase trafficking in S. cerevisiae: a useful model to dissect the microtubule network involvement of viral protein nuclear import

Cited by 24 publications

References 53 publications

A Role for Dynein in the Inhibition of Germ Cell Proliferative Fate

A Role for Dynein in the Inhibition of Germ Cell Proliferative Fate

Dynein Regulators Are Important for Ecotropic Murine Leukemia Virus Infection

Functional Evidence of the Involvement of the Dynein Light Chain DYNLRB2 in Murine Leukemia Virus Infection

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