人类逆转座子（LINE-1）是基因组内存在的一类能够自主转座的遗传物质，占人类基因组的17%。他们其中的大多数作为“基因化石”，已经失去了转座活性，但还存在80-100个活跃转座的LINE-1分子，不时的在人类基因组中发生跳跃。LINE-1的活跃转座会对于基因组的稳定性带来很多压力。基因组的稳定性和进化是一对相互依存的矛盾关系，人类的健康生存需要基因组保持相对的稳定，而生命体的进化又依赖着基因组突变的发生。正常的情况下，机体有严密的调控机制来限制其活跃转座。一旦调节机制出现异常，将会引发基因重组，转录异常等不稳定现象，并导致一系列疾病的发生，例如先天性免疫疾病，精神类疾病以及各类癌症等。

现有研究表明，生物体进化出了多种限制LINE-1逆转座的机制，包括对于LINE-1基因5’UTR区的高度甲基化，小RNA干扰，激活自噬途径等多种方式。除此之外，许多抑制病毒的宿主限制因子对于LINE-1逆转座的也有明显的调控作用。已有多个课题组进行了研究，例如APOBACE3家族蛋白，MOV10，SAMHD1，TREX1，RNASLE，ZAP等。Mx家族是一类重要的宿主限制因子，也是一类ISG。MxA的抗病毒功能研究开始的比较早，能够抑制多种病毒复制，但对于HIV-1没有调控作用。MxB是近年来发现的具有明显抑制HIV-1复制活性的宿主限制因子，主要通过结合Caspid蛋白来抑制HIV-1的脱衣壳作用。近期又有MxB抑制HCV，HBV和HSV的报道。此前，有研究报道了对于一系列ISGs调控LINE-1报告系统转座活性的筛选中提到，MxB具有明显的抑制LINE-1转座的能力，但其作用活性位点及机制还不清楚。研究MxB调控LINE-1逆转座的活性位点以及作用机制不仅可以解释生命体调控LINE-1逆转座机制这一重要生命科学问题，也对MxB抑制病毒的机制以及其在细胞内扮演的角色意义有了更深层次的推动。

本论文主要围绕MxB对于LINE-1逆转座作用的抑制作用，主要活性位点以及作用机制进行研究。研究发现，MxB无论是对于LINE-1报告系统，还是内源性LINE-1的逆转座都有明显的抑制作用，而MxA则没有这种抑制作用。这种抑制作用需要MxB的NLS区的定位作用，GTPase的结合活性，以及形成寡聚化的活性位点。进一步研究表明，MxB可与ORF1p发生相互作用，并且会与ORF1所在的SGs形成共定位和相互作用，进而导致ORF1p入核的减少。实验发现siRNA敲低TIA1或G3BP1后，MxB抑制LINE-1的作用减弱，证明MxB抑制LINE-1的逆转座机制依赖于将ORF1p隔离至SGs，从而减少了ORF1p的入核。

鉴于MxB对于LINE-1逆转座有明显的抑制作用，我们又利用另外一种内源性逆转录病毒IAP和MusD进行了实验，表明MxB有广泛的抑制内源性逆转录病毒的作用。在Mx蛋白进化的过程中，灵长类动物的MxB与人的MxB高度同源，而在小鼠中只存在与MxA同源的Mx1和Mx2。从进化角度区分析Mx蛋白的抗LINE-1逆转座能力，发现与人MxB同源的恒河猴MxB和非洲绿猿MxB均能够有效的抑制LINE-1的逆转座，而与人MxA同源的小鼠Mx1和Mx2都没有这个抑制能力。另外对于小鼠的内源性逆转录病毒IAP和MusD，恒河猴和非洲绿猿的MxB都有抑制其转座的能力，而小鼠的Mx1和Mx2却没有抑制的能力。这也表明，在进化水平上，MxB具有广泛的抗转座以及保护基因组稳定性的属性。

综上所述，MxB作为一种抗病毒宿主限制因子，同样具有显著的抑制LINE-1逆转座子和内源性逆转录病毒的功效，通过限制其ORF1p的入核，来调控细胞内LINE-1逆转座子的异常水平转座，从而维持细胞基因组的稳定。

Long interspersed element 1 (LINE-1) is the only autonomously active transposable element in the human genome, and account for approximately 17%. Great majority of L1 elements are molecular fossils that are no longer capable of mobilization, LINE-1 still has approximately 80-100 active copies in human genome. Retrotransposition of L1 can result in significant deletions and mutations of genomic sequence, and impacts genomic stability. Genomic stability and human evolution are interdependent and contradictory. Survival of healthy human requires the relative stability of the genome, but the evolution of life depends on mutations. Once overactive of LINE-1, it will cause many of deseases, such as autoimmunity disease, neurological disorders and cancers.

Given the mutagenic nature of LINE-1 retrotransposition, cells have developed various defense mechanisms to restrict LINE-1 mobilization. DNA methylation of 5’UTR, RNA interference dependent manner, and active of autophagy pathway are effective manners of control. One arsenal of mechanisms are provided by innate immune factors that have been shown to inhibit virus infections, such as APOBACE3 family, MOV10, SAMHD1, TREX1, RNASLE, ZAP. MxA and MxB are dynamin-like large GTPases. They have been reported to inhibit distinct groups of viruses by different mechanisms. MxA is cytoplasmic, inhibits a plethora of viruses from diverse families, but not HIV-1. In contrast, much fewer viruses have been reported to be restricted by MxB which is is located to the nuclear envelope. MxB, but not MxA, inhibits the replication of HIV-1 in cell culture. It was conceivable that MxB would target the viral capsid after its entry into the cell. Resently, other studies showed that MxB can also inhibit HCV, HBV and HSV replication in cell. In 2015, a research group screen many viral restriction factors of ISGs, detected than MxB can inhibit LINE-1-EGFP reporter (99-PUR-RPS-EGFP) activity, but the active region and the mechanism is unclear. To research the mechanism and active region of MxB inhibit LINE-1 retrotransposition can not only promote the development of endogenouse gene elements regulation, but also provide reference to MxB restrict virus and explain the role of MxB in cell life.

Here, we report that a cellular antiviral protein, myxovirus resistance protein B (MxB), restricts the mobilization of LINE-1. This function of MxB requires the nuclear localization signal located at its N-terminus, its GTPase activity and its ability to form oligomers. We further found that MxB associates with LINE-1 protein ORF1p and enhances sequestration of ORF1p to G3BP1-containing cytoplasmic granules. Since knockdown of stress granule marker proteins G3BP1 or TIA1 abolishes MxB inhibition of LINE-1, we conclude that MxB engages stress granule components to effectively stall LINE-1 proteins within the cytoplasmic granules, thus prevent LINE-1 from entering the nucleus to attempt retrotransposition.

Futher more, we next determined whether MxB are required on the inhibition of endogenous retroviruses IAP and MusD. Human MxB can also inhibit IAP and MusD significantly. We also interested in LINE-1 inhibition potency in other species. African green monkey (AGM) and Macaca mulatta (MAC), MxB have strong anti-LINE-1 activity, but the MxA homologue Mx1 and Mx2 from mouse can not impact LINE-1 mobilization, the same phenomenon was detected in IAP and MusD replication. Thus, LINE-1 and endogenous retroviruses IAP and MusD inhibition appears to be a conserved feature for primates MxB.

Above all, MxB is an antiviral host factor, also has the effect of significantly inhibiting LINE-1 retrotransposon and endogenous retroviruses. By restricting ORF1p import into the nucleus, MxB regulates the abnormal transposition of LINE-1 in cells, thus maintaining the stability of the cell genome.