PDF(Pubmed)
Abstract：
The sterile alpha motif and histidine-aspartate (HD) domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara-C) resistance in several haematological malignancies. Targeting SAMHD1\'s ara-CTPase activity has recently been demonstrated to enhance ara-C efficacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMG-box containing protein 11 (SOX11) as a novel direct binding partner and first known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Co-immunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identified SAMHD1 as the top SOX11 interaction partner which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar affinity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara-C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identified SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its first known endogenous inhibitor with potentially important implications for clinical therapy stratification.
摘要：
含有蛋白1（SAMHD1）的无菌α基序和组氨酸-天冬氨酸（HD）结构域是脱氧核苷三磷酸三磷酸水解酶，具有ara-CTPase活性，可在几种血液恶性肿瘤中赋予阿糖胞苷（ara-C）抗性。最近已证明靶向SAMHD1的ara-CTPase活性可增强急性髓细胞性白血病的ara-C疗效。这里,我们确定了转录因子SRY相关的含HMG-box的蛋白11(SOX11)是一种新型的直接结合伴侣,也是首个已知的SAMHD1内源性抑制剂.SOX11不仅在套细胞淋巴瘤（MCL）中异常表达，还有一些伯基特淋巴瘤。在MCL细胞系中SOX11的共免疫沉淀随后进行质谱分析,将SAMHD1鉴定为顶部SOX11相互作用配偶体,其通过邻近连接测定进行验证。体外，SAMHD1以低微摩尔亲和力与SOX11的HMG盒结合。原位交联研究进一步表明,SOX11-SAMHD1结合导致SAMHD1的四聚减少。功能上,SOX11的表达以剂量依赖性方式抑制SAMHD1ara-CTPase活性，导致细胞系和SOX11诱导型MCL小鼠模型中的ara-C致敏。在SOX11阴性MCL中，SOX11介导的ara-CTPase抑制可以通过添加最近鉴定的SAMHD1抑制剂羟基脲来模拟。一起来看,我们的研究结果将SOX11确定为一种新型SAMHD1相互作用伴侣及其首个已知的内源性抑制剂,对临床治疗分层具有潜在的重要意义.
