SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV
SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV
复制标题
DOI：
10.1128/jvi.03202-15
复制
发表时间：
2016-04-01
影响因子：
5.4
通讯作者：
Schwartz, Olivier
中科院分区：
文献类型：
--
作者：
Donahue, Daniel A.;Amraoui, Sonia;Schwartz, Olivier
在之前的干扰素刺激基因筛选中，SUN2被证明以一种未确定的方式抑制HIV-1感染。SUN2是一种内核膜蛋白，属于核骨架和细胞骨架复合体的连接物。我们在这里分析了SUN2在HIV感染中的作用。我们报告说，与最初认为的相反，SUN2不是由I型干扰素诱导的，并且SUN2沉默不调节HIV感染。然而，在细胞系和原代单核细胞来源的树突状细胞中过表达的SUN2可以抑制HIV的复制，但不能抑制小鼠白血病病毒或基孔肯雅病毒的复制。我们确定了不受SUN2影响的HIV-1和HIV-2毒株，这表明这种影响是特定的病毒成分或辅助因子所特有的。有趣的是，SUN2的过表达诱导了一个不影响细胞活力的多小叶花状核形状，类似于从HTLV-I相关的成人T细胞白血病或早衰症患者中分离出来的细胞。核形状的改变和HIV的抑制都映射到与核层相互作用的SUN2的核质结构域。这种对HIV复制的阻断发生在逆转录和核进入之间，传代实验选择了衣壳(CA)中的单个氨基酸变化，导致对过度表达的SUN2的抗性。此外，通过化学抑制或沉默亲环素A(CypA)以及CA突变病毒，我们发现CypA参与了SUN2对HIV感染的阻断。我们的结果表明，SUN2的过表达扰乱了HIV感染的核形状和早期事件。IMPORTANCECells编码干扰病毒复制的蛋白质，其中一些已经在过表达筛选中被发现。SUN2是一种核膜蛋白，在这样的筛查中显示出抑制艾滋病毒感染，但它是如何阻止艾滋病毒感染的尚不清楚。我们发现，SUN2的过度表达在核进入之前阻止了某些HIV毒株的感染。病毒衣壳蛋白的突变产生了抗SUN2的艾滋病毒。此外，SUN2对艾滋病毒感染的抑制涉及亲环素A，这是一种结合艾滋病毒衣壳并指导后续感染步骤的蛋白质。我们还发现，SUN2的过度表达实质上改变了细胞核的形状，导致许多花朵状的细胞核。HIV的抑制和核形状的变形都需要与核层相互作用的SUN2结构域。我们的结果表明，SUN2干扰艾滋病毒感染，并突出了核形状和病毒感染之间的新联系。
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.