The diverse functional LINCs of the nuclear envelope to the cytoskeleton and chromatin

Rothballer, Andrea; Kutay, Ulrike

doi:10.1007/s00412-013-0417-x

Cited by 119 publications

(106 citation statements)

References 159 publications

(330 reference statements)

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“…1A; discussed in recent reviews, e.g. Gundersen and Worman, 2013;Rothballer and Kutay, 2013;Simon and Wilson, 2011;Sosa et al, 2013). Cell-cell interactions link to the cytoskeleton through tight junctions and adherens junctions that tether to actin, and through desmosome complexes that interact with cytoplasmic intermediate filaments, such as keratin (Jamora and Fuchs, 2002).…”

Section: Mechanotransduction To the Nucleus -Downstream Of Ecm And Laminmentioning

confidence: 99%

The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue

Swift

Discher

2014

Journal of Cell Science

187

165

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How cells respond to physical cues in order to meet and withstand the physical demands of their immediate surroundings has been of great interest for many years, with current research efforts focused on mechanisms that transduce signals into gene expression. Pathways that mechano-regulate the entry of transcription factors into the cell nucleus are emerging, and our most recent studies show that the mechanical properties of the nucleus itself are actively controlled in response to the elasticity of the extracellular matrix (ECM) in both mature and developing tissue. In this Commentary, we review the mechano-responsive properties of nuclei as determined by the intermediate filament lamin proteins that line the inside of the nuclear envelope and that also impact upon transcription factor entry and broader epigenetic mechanisms. We summarize the signaling pathways that regulate lamin levels and cell-fate decisions in response to a combination of ECM mechanics and molecular cues. We will also discuss recent work that highlights the importance of nuclear mechanics in niche anchorage and cell motility during development, hematopoietic differentiation and cancer metastasis, as well as emphasizing a role for nuclear mechanics in protecting chromatin from stress-induced damage.

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Section: Mechanotransduction To the Nucleus -Downstream Of Ecm And Laminmentioning

confidence: 99%

The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue

Swift

Discher

2014

Journal of Cell Science

187

165

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“…inker of nucleoskeleton and cytoskeleton (LINC) complexes connect the nucleus to the cytoskeleton and are evolutionarily conserved in eukaryotes from budding and fission yeasts and Caenorhabditis elegans to D. melanogaster, plants, and mammals (1). The LINC complex is defined by the interaction of KASH domain proteins and SUN domain proteins in the perinuclear space.…”

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confidence: 99%

SUN2 Silencing Impairs CD4 T Cell Proliferation and Alters Sensitivity to HIV-1 Infection Independently of Cyclophilin A

Donahue

Porrot

Couespel

2017

J Virol

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Linker of nucleoskeleton and cytoskeleton (LINC) complexes connect the nucleus to the cytoskeleton in eukaryotic cells. We previously reported that the overexpression of SUN2, an inner nuclear membrane protein and LINC complex component, inhibits HIV infection between the steps of reverse transcription and nuclear import in a capsid-specific manner. We also reported that SUN2 silencing does not modulate HIV infection in several cell lines. Silencing of SUN2 was recently reported to decrease HIV infection of CD4 T cells, an effect which was suggested to result from modulation of cyclophilin A (CypA)-dependent steps of HIV infection. We confirm here that HIV infection of primary CD4 T cells is compromised in the absence of endogenous SUN2, and we extend these findings to additional viral strains. However, we find that CypA is not required for the decreased infection observed in SUN2-silenced cells and, conversely, that endogenous SUN2 is not required for the well-documented positive modulation of HIV infection by CypA. In contrast, CD4 T cells lacking SUN2 exhibit a considerable defect in proliferative capacity and display reduced levels of activation markers and decreased viability. Additionally, SUN2-silenced CD4 T cells that become infected support reduced levels of viral protein expression. Our results demonstrate that SUN2 is required for the optimal activation and proliferation of primary CD4 T cells and suggest that the disruption of these processes explains the contribution of endogenous SUN2 to HIV infection in primary lymphocytes.IMPORTANCE Linker of nucleoskeleton and cytoskeleton (LINC) complexes connect the nucleus to the cytoskeleton. We previously reported that the overexpression of the LINC complex protein SUN2 inhibits HIV infection by targeting the viral capsid and blocking infection before the virus enters the nucleus. A recent report showed that the depletion of endogenous SUN2 in primary CD4 T cells results in decreased HIV infection and that this involves cyclophilin A (CypA), a host protein that interacts with the capsid of HIV to promote infection. We confirm that HIV infection is reduced in CD4 T cells lacking SUN2, but we find no role for CypA. Instead, SUN2 silencing results in CD4 T cells with decreased viability and much lower proliferation rates. Our results show that SUN2 is required for optimal CD4 T cell activation and proliferation and explain the reduced level of HIV infection in the absence of SUN2.KEYWORDS CD4 T cell, SUN2, human immunodeficiency virus L inker of nucleoskeleton and cytoskeleton (LINC) complexes connect the nucleus to the cytoskeleton and are evolutionarily conserved in eukaryotes from budding and fission yeasts and Caenorhabditis elegans to D. melanogaster, plants, and mammals (1). The LINC complex is defined by the interaction of KASH domain proteins and SUN

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“…This SUN-KASH interaction defines the LINC complex, which forms a physical bridge between the cytoplasm and the nucleus. LINC complexes play important roles in many cellular processes in eukaryotes, including control of nuclear size, shape, anchoring, and migration; transmission of forces across the nuclear membrane; cell polarization; cytoskeleton organization; chromosome tethering; and DNA repair (reviewed in references [37][38][39][40].…”

mentioning

confidence: 99%

SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

Donahue

Amraoui

Nunzio

et al. 2016

J Virol

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In a previous screen of putative interferon-stimulated genes, SUN2 was shown to inhibit HIV-1 infection in an uncharacterized manner. SUN2 is an inner nuclear membrane protein belonging to the linker of nucleoskeleton and cytoskeleton complex. We have analyzed here the role of SUN2 in HIV infection. We report that in contrast to what was initially thought, SUN2 is not induced by type I interferon, and that SUN2 silencing does not modulate HIV infection. However, SUN2 overexpression in cell lines and in primary monocyte-derived dendritic cells inhibits the replication of HIV but not murine leukemia virus or chikungunya virus. We identified HIV-1 and HIV-2 strains that are unaffected by SUN2, suggesting that the effect is specific to particular viral components or cofactors. Intriguingly, SUN2 overexpression induces a multilobular flower-like nuclear shape that does not impact cell viability and is similar to that of cells isolated from patients with HTLV-I-associated adult T-cell leukemia or with progeria. Nuclear shape changes and HIV inhibition both mapped to the nucleoplasmic domain of SUN2 that interacts with the nuclear lamina. This block to HIV replication occurs between reverse transcription and nuclear entry, and passaging experiments selected for a single-amino-acid change in capsid (CA) that leads to resistance to overexpressed SUN2. Furthermore, using chemical inhibition or silencing of cyclophilin A (CypA), as well as CA mutant viruses, we implicated CypA in the SUN2-imposed block to HIV infection. Our results demonstrate that SUN2 overexpression perturbs both nuclear shape and early events of HIV infection. IMPORTANCECells encode proteins that interfere with viral replication, a number of which have been identified in overexpression screens. SUN2 is a nuclear membrane protein that was shown to inhibit HIV infection in such a screen, but how it blocked HIV infection was not known. We show that SUN2 overexpression blocks the infection of certain strains of HIV before nuclear entry. Mutation of the viral capsid protein yielded SUN2-resistant HIV. Additionally, the inhibition of HIV infection by SUN2 involves cyclophilin A, a protein that binds the HIV capsid and directs subsequent steps of infection. We also found that SUN2 overexpression substantially changes the shape of the cell's nucleus, resulting in many flower-like nuclei. Both HIV inhibition and deformation of nuclear shape required the domain of SUN2 that interacts with the nuclear lamina. Our results demonstrate that SUN2 interferes with HIV infection and highlight novel links between nuclear shape and viral infection.

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The diverse functional LINCs of the nuclear envelope to the cytoskeleton and chromatin

Cited by 119 publications

References 159 publications

The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue

The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue

SUN2 Silencing Impairs CD4 T Cell Proliferation and Alters Sensitivity to HIV-1 Infection Independently of Cyclophilin A

SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

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