Nuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV Replication

Lahaye, Xavier; Satoh, Takeshi; Gentili, Matteo; Cerboni, Silvia; Silvin, Aymeric; Conrad, Cécile; Ahmed–Belkacem, Abdelhakim; Rodriguez, Elisa C.; Guichou, Jean-François; Bosquet, Nathalie; Piel, Matthieu; Grand, Roger Le; King, Megan C.; Pawlotsky, Jean‐Michel; Manel, Nicolas

doi:10.1016/j.celrep.2016.03.074

Cited by 41 publications

(75 citation statements)

References 59 publications

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“…Single-round infection was decreased by an average of 2-fold in the absence of SUN2 (Fig. 3A and B), consistent with data reported previously (9). We next asked whether CypA might be involved in this modest effect.…”

Section: Resultssupporting

confidence: 78%

“…Through the use of CypA inhibitors, those authors obtained results suggesting that SUN2 facilitates HIV infection by modulating the positive effects of CypA on the virus. However, the positive effects of CypA on HIV infection have long been known to alter levels of reverse transcripts, 2-long terminal repeat (LTR) circles, and integrated DNA (13)(14)(15)(16)(17)(18), whereas levels of viral DNA forms were unchanged in SUN2-depleted cells despite reduced levels of productive infection (9). This raises the possibility that alternative mechanisms might explain the decreased infection of cells depleted of SUN2.…”

mentioning

confidence: 65%

“…In that same study, we found no role for endogenous SUN2 during infection of several adherent cell lines (8). In contrast, Lahaye and colleagues recently reported that endogenous SUN2 acts as a cofactor for HIV infection of primary CD4 T cells and MDDCs (9). Silencing of SUN2 led to a modest decrease in single-round HIV infection, while spreading infection was strongly impacted.…”

mentioning

confidence: 73%

“…To address the role of endogenous SUN2 during HIV infection of primary CD4 T cells, we first examined the consequences of SUN2 silencing on CD4 T cell health. Freshly isolated CD4 T cells were activated with anti-CD2/CD3/CD28 beads and were then transduced with lentiviral particles encoding short hairpin RNA (shRNA) against two different regions of SUN2 (shSUN2#4 and shSUN2#5) or a control shRNA targeting LacZ (shLacZ), as reported previously (9). SUN2 was routinely undetectable by 5 to 6 days postransduction (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…An overexpression screen of putative interferon-stimulated genes (ISGs) found that SUN2 inhibited HIV-1 infection of a T cell line through unknown mechanisms (7). While we and others subsequently found that SUN2 was not induced by interferon in human cells (8,9), we reported that its overexpression inhibits infection by HIV-1 and HIV-2 in multiple cell lines and in monocyte-derived dendritic cells (MDDCs) (8). This inhibition occurred at the time of or before viral nuclear import and could be circumvented by several naturally occurring HIV strains or by a single point mutation in the viral capsid.…”

mentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 78%

mentioning

confidence: 65%

mentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Roles of the nucleus in leukocyte migration

Chen

Chang

2022

Journal of Leukocyte Biology

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Leukocytes patrol our bodies in search of pathogens and migrate to sites of injury in response to various stimuli. Rapid and directed leukocyte motility is therefore crucial to our immunity. The nucleus is the largest and stiffest cellular organelle and a mechanical obstacle for migration through constrictions. However, the nucleus is also essential for 3D cell migration. Here, we review the roles of the nucleus in leukocyte migration, focusing on how cells deform their nuclei to aid cell motility and the contributions of the nucleus to cell migration. We discuss the regulation of the nuclear biomechanics by the nuclear lamina and how it, together with the cytoskeleton, modulates the shapes of leukocyte nuclei. We then summarize the functions of nesprins and SUN proteins in leukocytes and discuss how forces are exerted on the nucleus. Finally, we examine the mechanical roles of the nucleus in cell migration, including its roles in regulating the direction of migration and path selection.

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Downregulation of SUN2 promotes metastasis of colon cancer by activating BDNF/TrkB signalling by interacting with SIRT1

Liu

Yuan

et al. 2021

The Journal of Pathology

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Distant metastasis is the major cause of colon cancer (CC) treatment failure. SAD1/UNC84 domain protein-2 (SUN2) is a key component of linker of the nucleoskeleton and cytoskeleton (LINC) complexes that may be relevant for metastasis in several cancers. Here, we first confirmed that SUN2 levels were significantly lower in primary CC tissues and distant metastasis than in normal colon tissues, and high SUN2 expression predicted good overall survival. Overexpression of SUN2 or knockdown of SUN2 inhibited or promoted cell migration and invasion in vitro, respectively. Moreover, silencing of SUN2 promoted metastasis in vivo. Mechanistically, we showed that SUN2 exerts its tumour suppressor functions by decreasing the expression of brain derived neurotrophic factor (BDNF) to inhibit BDNF/ tropomyosin-related kinase B (TrkB) signalling. Additionally, SUN2 associated with SIRT1 and increased the acetylation of methyl-CpG binding protein 2 (MeCP2) to increase its occupancy at the BDNF promoter. Taken together, our findings indicate that SUN2 is a key component in CC progression that acts by inhibiting metastasis and that novel SUN2-SIRT1-MeCP2-BDNF signalling may prove to be useful for the development of new strategies for treating patients with CC.

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Nuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV Replication

Cited by 41 publications

References 59 publications

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

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

Roles of the nucleus in leukocyte migration

Downregulation of SUN2 promotes metastasis of colon cancer by activating BDNF/TrkB signalling by interacting with SIRT1

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