Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7

Fassati, Ariberto; Görlich, Dirk; Harrison, Ian; Zaytseva, Lyubov; Mingot, José-Manuel

doi:10.1093/emboj/cdg357

Cited by 158 publications

(170 citation statements)

References 54 publications

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“…Nuclear import in the human cell is orchestrated by a plethora of karyopherins, comprising both broad spectrum and highly specialized transporters. Several of these have been suggested to take part in HIV nuclear import, in particular importin-␣/␤ (8 -10), importin-␣3 (11), and importin-7 (12)(13)(14)(15). In 2008, transportin-SR2 (TRN-SR2, transportin-3, Tnpo3), encoded by the TNPO3 gene, was independently identified as a cellular cofactor of HIV in two genome-wide siRNA screens (16,17) and picked up as a specific binding partner of HIV IN (18).…”

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confidence: 99%

The HIV-1 Integrase Mutant R263A/K264A Is 2-fold Defective for TRN-SR2 Binding and Viral Nuclear Import

Houwer

Demeulemeester

Thys

et al. 2014

Journal of Biological Chemistry

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Background: Whether the TRN-SR2/HIV-1 IN interaction mediates the nuclear import of HIV is controversial. Results: The replication-defective HIV integrase mutant INR263A/K264A displays a 2-fold reduction in interaction with TRN-SR2 and PIC nuclear import. Conclusion:The HIV-IN TRN-SR2 protein-protein interaction is important for HIV nuclear import. Significance: The IN/TRN-SR2 interaction interface is a potential target for future antiviral therapy.

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confidence: 99%

The HIV-1 Integrase Mutant R263A/K264A Is 2-fold Defective for TRN-SR2 Binding and Viral Nuclear Import

Houwer

Demeulemeester

Thys

et al. 2014

Journal of Biological Chemistry

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“…Because not only H1 is imported into the nucleus by the Imp␤⅐Imp7 heterodimer but also the integrase of human immunodeficiency virus-1 (HIV-1-IN) (29), in this case with Imp7 being the protagonist and Imp␤ only a minor player, it will be of major importance to obtain crystal structures of H1 and HIV-1-IN in complex with Imp␤⅐Imp7 to understand how in detail Imp7 is regulated by Imp␤ and how HIV-1-IN adopts the features of cellular cargoes such as H1 to make use of a very similar import pathway as well. …”

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confidence: 99%

Thermodynamic Analysis of H1 Nuclear Import

Wohlwend

Strasser

Dickmanns

et al. 2007

Journal of Biological Chemistry

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The nuclear import of H1 linker histones is mediated by a heterodimer of transport receptors, known as importin␤ and importin7. Interestingly, both importins separately interact with H1, but only as a dimer they facilitate the translocation through the nuclear pore. We identified the H1 binding site of importin7, comprising two extended acidic loops near the C terminus of importin7. The analysis of the H1 import complex assembly by means of isothermal titration calorimetry revealed that the formation of a receptor heterodimer in vitro is an enthalpy-driven process, whereas subsequent binding of H1 to the heterodimer is entropy-driven. Furthermore, we show that the importin␤ binding domain of importin7 plays a key role in the activation of importin7 by importin␤. This process is allosterically regulated by importin␤ and accounts for a specific tuning of the activity of the importin␤⅐importin7 heterodimer. The results presented here provide new insights into cellular strategies to even energy balances in nuclear import and point toward a general regulation of importin␤-related nuclear import processes.The nuclear transport machinery represents one of the major transport systems in eukaryotic cells connecting the nucleus and the cytosol by bridging the nuclear envelope. Nuclear pore complexes (NPCs) 2 are embedded in the nuclear envelope and provide the channels for nuclear transport. NPCs have a dual function; whereas solutes, ions and small macromolecules (20 -40 kDa) are allowed to diffuse passively through the nuclear pore, larger macromolecules or such, whose transfer has to be tightly controlled, are transported by specific, soluble transport receptors in a signal-dependent manner (for review, see Refs. 1-4). The majority of known transport signals are specifically recognized by members of the importin␤/karyopherin␤ protein superfamily shuttling between nucleus and cytosol, also known as importins and exportins. They are composed of a number of helix-turn-helix motifs termed HEAT tandem repeats, which pack side by side in an almost parallel fashion, forming elongated molecules with a superhelical twist (5-8). Besides one or more substrate binding sites, these proteins additionally comprise a binding site for the small GTPase Ran (9). Ran represents the central mediator of directionality of nucleocytoplasmic trafficking. Its low intrinsic GTPase activity allows for a rigid control of GTP hydrolysis. The cytosolic GTPase-activating protein RanGAP1 acts as activator of Ran; the additional factors RanBP1 and RanBP2 act as GTPase enhancers and further stimulate Ran's GTP hydrolysis rate. Due to the nucleocytoplasmic compartmentalization of the regulatory factors, with RanGAP in the cytosol and RanGEF in the nucleus, a steep gradient of RanGTP is established across the nuclear envelope with high concentrations in the nucleus and low ones in the cytosol. The RanGTP gradient across the nuclear envelope is thought to provoke a unidirectional translocation of cargoes through the NPC; in terms of nuclear import, bindi...

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“…A number of cargoes have been identified that require Imp-7 for nuclear translocation. Some are general cellular proteins, such as ribosomal proteins (Jäkel et al 1999;Fassati et al 2003;Freedman and Yamamoto 2004), while others are transcription factors that are imported in response to stimulation, including both vertebrate and Drosophila ERK (Lorenzen et al 2001;Michailovici et al 2014). However, we did not observe an effect of Msk reduction on diphosphorylated ERK (dpERK) subcellular localization or protein levels in the myoblasts ( Figure S4 in File S1).…”

Section: Discussionmentioning

confidence: 62%

Adult Muscle Formation Requires Drosophila Moleskin for Proliferation of Wing Disc-Associated Muscle Precursors

et al. 2017

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Adult muscle precursor (AMP) cells located in the notum of the larval wing disc undergo rapid amplification and eventual fusion to generate the Drosophila melanogaster indirect flight muscles (IFMs). Here we find that loss of Moleskin (Msk) function in these wing disc-associated myoblasts reduces the overall AMP pool size, resulting in the absence of IFM formation. This myoblast loss is due to a decrease in the AMP proliferative capacity and is independent of cell death. In contrast, disruption of Msk during pupal myoblast proliferation does not alter the AMP number, suggesting that Msk is specifically required for larval AMP proliferation. It has been previously shown that Wingless (Wg) signaling maintains expression of the Vestigial (Vg) transcription factor in proliferating myoblasts. However, other factors that influence Wg-mediated myoblast proliferation are largely unknown. Here we examine the interactions between Msk and the Wg pathway in regulation of the AMP pool size. We find that a myoblast-specific reduction of Msk results in the absence of Vg expression and a complete loss of the Wg pathway readout b-catenin/Armadillo (Arm). Moreover, msk RNA interference knockdown abolishes expression of the Wg target Ladybird (Lbe) in leg disc myoblasts. Collectively, our results provide strong evidence that Msk acts through the Wg signaling pathway to control myoblast pool size and muscle formation by regulating Arm stability or nuclear transport.

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Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7

Cited by 158 publications

References 54 publications

The HIV-1 Integrase Mutant R263A/K264A Is 2-fold Defective for TRN-SR2 Binding and Viral Nuclear Import

The HIV-1 Integrase Mutant R263A/K264A Is 2-fold Defective for TRN-SR2 Binding and Viral Nuclear Import

Thermodynamic Analysis of H1 Nuclear Import

Adult Muscle Formation Requires Drosophila Moleskin for Proliferation of Wing Disc-Associated Muscle Precursors

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