CeMM - Research Center for Molecular Medicine, Austrian Academy of Sciences, Lazarettgasse 14, Vienna, Austria.
Hum Mutat. 2012 Jul;33(7):1116-22. doi: 10.1002/humu.22087. Epub 2012 Apr 16.
Aicardi-Goutières syndrome (AGS) is a rare inherited autoimmune disease caused by mutations in genes encoding the RNase H2 subunits A, B, and C; the DNase three prime repair exonuclease 1 (TREX1); and sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1). Using unbiased affinity purification coupled to protein mass spectrometry, we identify SAMHD1 as a nucleic-acid-binding protein displaying a preference for RNA over DNA. In contrast to TREX1 and the RNase H2 complex, SAMHD1 has no obvious nuclease activity. In addition, interrogating truncation mutants of SAMHD1 observed in AGS patients, we map the nucleic-acid-binding domain to residues 164-442, thus overlapping with the HD domain. Furthermore, we show that although wild-type SAMHD1 displays almost exclusive nuclear localization, 11 of 12 SAMHD1 mutants show at least partial mislocalization to the cytosol. Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease.
Aicardi-Goutières 综合征（AGS）是一种罕见的遗传性自身免疫性疾病，由编码 RNase H2 亚基 A、B 和 C 的基因、核酸外切酶 3'末端修复（TREX1）和含有 sterile alpha motif（SAM）结构域和 HD 结构域的蛋白 1（SAMHD1）的突变引起。通过无偏的亲和纯化结合蛋白质质谱分析，我们鉴定出 SAMHD1 是一种具有 RNA 偏好性的核酸结合蛋白，而不是 DNA。与 TREX1 和 RNase H2 复合物不同，SAMHD1 没有明显的核酸酶活性。此外，我们还研究了在 AGS 患者中观察到的 SAMHD1 截断突变体，将核酸结合域定位到残基 164-442，与 HD 结构域重叠。此外，我们表明，尽管野生型 SAMHD1 显示几乎完全的核定位，但 12 个 SAMHD1 突变体中的 11 个至少部分错误定位到细胞质。总的来说，这些数据表明 SAMHD1 在细胞核中具有一定的功能，如果其突变导致 SAMHD1 向细胞质的积累，就会引发自身免疫性疾病。
