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
复制标题
DOI：
10.1128/jvi.02303-16
复制
发表时间：
2017-03-01
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;Porrot, FranOoise;Schwartz, Olivier
在真核细胞中，核骨架和细胞骨架(LINC)复合体连接细胞核和细胞骨架。我们先前报道，SUN2是一种内核膜蛋白和LINC复合体成分，它的过表达以衣壳特异的方式在逆转录和核输入步骤之间抑制HIV感染。我们还报道，SUN2沉默并不调节几种细胞系中的HIV感染。最近报道，沉默SUN2可以减少HIV对CD4T细胞的感染，这一作用可能是通过调节亲环素A(CypA)依赖的HIV感染步骤来实现的。我们在此证实，在没有内源性SUN2的情况下，HIV对原代CD4T细胞的感染是危险的，我们将这些发现扩展到其他病毒株。然而，我们发现在SUN2沉默的细胞中观察到的感染减少并不需要CypA，相反，内源性SUN2不是CypA对HIV感染进行积极调制所必需的。相比之下，缺乏SUN2的CD4T细胞在增殖能力方面表现出相当大的缺陷，并表现出激活标志水平的降低和活性的降低。此外，SUN2使感染的CD4T细胞沉默，支持病毒蛋白表达水平的降低。我们的结果表明，SUN2是原代CD4T细胞最佳激活和增殖所必需的，并提示这些过程的破坏解释了内源性SUN2在初级淋巴细胞中对HIV感染的贡献。核骨架和细胞骨架(LINC)复合体的重要连接物连接细胞核和细胞骨架。我们此前曾报道，LINC复合体蛋白SUN2的过表达通过靶向病毒衣壳并在病毒进入细胞核之前阻止感染来抑制艾滋病毒感染。最近的一份报告显示，原代CD4T细胞内源性SUN2的耗尽导致HIV感染的减少，这涉及到亲环素A(CypA)，这是一种与HIV衣壳相互作用的宿主蛋白，以促进感染。我们证实，在缺乏SUN2的CD4T细胞中，HIV感染减少，但我们发现CypA没有作用。相反，SUN2沉默会导致CD4T细胞活性降低，增殖率大大降低。我们的结果表明，SUN2是最佳的CD4T细胞激活和增殖所必需的，并解释了在没有SUN2的情况下HIV感染水平降低的原因。
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.