Koyama Takayoshi, Arias Juan Fernando, Iwabu Yukie, Yokoyama Masaru, Fujita Hideaki, Sato Hironori, Tokunaga Kenzo
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.
PLoS One. 2013 Dec 19;8(12):e84228. doi: 10.1371/journal.pone.0084228. eCollection 2013.
Alu and LINE-1 (L1), which constitute ~11% and ~17% of the human genome, respectively, are transposable non-LTR retroelements. They transpose not only in germ cells but also in somatic cells, occasionally causing cancer. We have previously demonstrated that antiretroviral restriction factors, human APOBEC3 (hA3) proteins (A-H), differentially inhibit L1 retrotransposition. In this present study, we found that hA3 members also restrict Alu retrotransposition at differential levels that correlate with those observed previously for L1 inhibition. Through deletion analyses based on the best-characterized hA3 member human APOBEC3G (hA3G), its N-terminal 30 amino acids were required for its inhibitory activity against Alu retrotransposition. The inhibitory effect of hA3G on Alu retrotransposition was associated with its oligomerization that was affected by the deletion of its N-terminal 30 amino acids. Through structural modeling, the amino acids 24 to 28 of hA3G were predicted to be located at the interface of the dimer. The mutation of these residues resulted in abrogated hA3G oligomerization, and consistently abolished the inhibitory activity of hA3G against Alu retrotransposition. Importantly, the anti-L1 activity of hA3G was also associated with hA3G oligomerization. These results suggest that the inhibitory activities of hA3G against Alu and L1 retrotransposition might involve a common mechanism.
Alu和LINE-1（L1）分别占人类基因组的约11%和约17%，它们是可转座的非LTR逆转录元件。它们不仅在生殖细胞中发生转座，也在体细胞中发生转座，偶尔会引发癌症。我们之前已经证明，抗逆转录病毒限制因子，即人类载脂蛋白B mRNA编辑酶催化多肽样蛋白3（hA3）家族蛋白（A - H），对L1逆转录转座具有不同程度的抑制作用。在本研究中，我们发现hA3家族成员对Alu逆转录转座也有不同程度的限制作用，且这些限制水平与之前观察到的对L1抑制作用的水平相关。基于特征最明确的hA3家族成员人类载脂蛋白B mRNA编辑酶催化多肽样蛋白3G（hA3G）进行缺失分析，发现其N端30个氨基酸是其抑制Alu逆转录转座活性所必需的。hA3G对Alu逆转录转座的抑制作用与其寡聚化有关，而N端30个氨基酸的缺失会影响其寡聚化。通过结构建模预测，hA3G的24至28位氨基酸位于二聚体界面。这些残基的突变导致hA3G寡聚化被消除，同时也消除了hA3G对Alu逆转录转座的抑制活性。重要的是，hA3G的抗L1活性也与其寡聚化有关。这些结果表明，hA3G对Alu和L1逆转录转座的抑制活性可能涉及共同机制。
