Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Biol Chem. 2011 Jul 29;286(30):26568-75. doi: 10.1074/jbc.M111.235721. Epub 2011 Jun 9.
The beneficial effects of DNA cytidine deamination by activation-induced deaminase (AID; antibody gene diversification) and APOBEC3G (retrovirus restriction) are tempered by probable contributions to carcinogenesis. Multiple regulatory mechanisms serve to minimize this detrimental outcome. Here, we show that phosphorylation of a conserved threonine attenuates the intrinsic activity of activation-induced deaminase (Thr-27) and APOBEC3G (Thr-218). Phospho-null alanine mutants maintain intrinsic DNA deaminase activity, whereas phospho-mimetic glutamate mutants are inactive. The phospho-mimetic variants fail to mediate isotype switching in activated mouse splenic B lymphocytes or suppress HIV-1 replication in human T cells. Our data combine to suggest a model in which this critical threonine acts as a phospho-switch that fine-tunes the adaptive and innate immune responses and helps protect mammalian genomic DNA from procarcinogenic lesions.
激活诱导的脱氨酶 (AID；抗体基因多样化) 和 APOBEC3G（逆转录病毒限制）对胞嘧啶脱氨的有益影响，可能会促进肿瘤发生。多种调节机制有助于将这种有害结果降至最低。在这里，我们表明磷酸化一个保守的苏氨酸可以减弱激活诱导的脱氨酶 (Thr-27) 和 APOBEC3G (Thr-218) 的固有活性。磷酸化缺失的丙氨酸突变体保持内在的 DNA 脱氨酶活性，而磷酸化模拟的谷氨酸突变体则没有活性。磷酸化模拟变体不能介导激活的小鼠脾 B 淋巴细胞中的同种型转换，或抑制人 T 细胞中的 HIV-1 复制。我们的数据结合表明，这个关键的苏氨酸作为一个磷酸化开关，精细调节适应性和先天免疫反应，并有助于保护哺乳动物基因组 DNA 免受致癌损伤。
