PDF(Pubmed)
Abstract：
Sterile alpha motif domain-containing proteins 9 and 9-like (SAMD9/9L) are associated with life-threatening genetic diseases in humans and are restriction factors of poxviruses. Yet, their cellular function and the extent of their antiviral role are poorly known. Here, we found that interferon-stimulated human SAMD9L restricts HIV-1 in the late phases of replication, at the posttranscriptional and prematuration steps, impacting viral translation and, possibly, endosomal trafficking. Surprisingly, the paralog SAMD9 exerted an opposite effect, enhancing HIV-1. More broadly, we showed that SAMD9L restricts primate lentiviruses, but not a gammaretrovirus (MLV), nor 2 RNA viruses (arenavirus MOPV and rhabdovirus VSV). Using structural modeling and mutagenesis of SAMD9L, we identified a conserved Schlafen-like active site necessary for HIV-1 restriction by human and a rodent SAMD9L. By testing a gain-of-function constitutively active variant from patients with SAMD9L-associated autoinflammatory disease, we determined that SAMD9L pathogenic functions also depend on the Schlafen-like active site. Finally, we found that the constitutively active SAMD9L strongly inhibited HIV, MLV, and, to a lesser extent, MOPV. This suggests that the virus-specific effect of SAMD9L may involve its differential activation/sensing and the virus ability to evade from SAMD9L restriction. Overall, our study identifies SAMD9L as an HIV-1 antiviral factor from the cell autonomous immunity and deciphers host determinants underlying the translational repression. This provides novel links and therapeutic avenues against viral infections and genetic diseases.
摘要：
含有无菌α基序结构域的蛋白9和9样蛋白(SAMD9/9L)与人类危及生命的遗传疾病有关,并且是痘病毒的限制因子。然而，它们的细胞功能和抗病毒作用的程度知之甚少。这里,我们发现干扰素刺激的人SAMD9L在复制的后期限制了HIV-1，在转录后和早熟阶段，影响病毒翻译，可能,内体运输。令人惊讶的是,模拟SAMD9产生了相反的效果，增强HIV-1。更广泛地说,我们发现SAMD9L限制灵长类慢病毒，但不是γ逆转录病毒（MLV），Nor2RNA病毒（沙粒病毒MOPV和弹状病毒VSV）。使用SAMD9L的结构建模和诱变，我们确定了人类和啮齿动物SAMD9L限制HIV-1所必需的保守的Schlafen样活性位点。通过测试SAMD9L相关自身炎症性疾病患者的功能增益组成型活性变异，我们确定SAMD9L的致病功能也取决于Schlafen样活性位点。最后,我们发现组成型活性SAMD9L强烈抑制HIV，MLV,and,在较小程度上，MOPV。这表明SAMD9L的病毒特异性作用可能涉及其差异激活/传感以及病毒逃避SAMD9L限制的能力。总的来说,我们的研究将SAMD9L从细胞自主免疫中鉴定为HIV-1抗病毒因子,并破译了翻译抑制的潜在宿主决定簇.这提供了针对病毒感染和遗传疾病的新联系和治疗途径。
