Varghese Sreeja, Cotter Michelle, Chevot Franciane, Fergus Claire, Cunningham Colm, Mills Kingston H, Connon Stephen J, Southern John M, Kelly Vincent P
School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
School of Chemistry, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
Nucleic Acids Res. 2017 Feb 28;45(4):2029-2039. doi: 10.1093/nar/gkw847.
Queuine is a modified pyrrolopyrimidine nucleobase derived exclusively from bacteria. It post-transcriptionally replaces guanine 34 in transfer RNA isoacceptors for Asp, Asn, His and Tyr, in almost all eukaryotic organisms, through the activity of the ancient tRNA guanine transglycosylase (TGT) enzyme. tRNA hypomodification with queuine is a characteristic of rapidly-proliferating, non-differentiated cells. Autoimmune diseases, including multiple sclerosis, are characterised by the rapid expansion of T cells directed to self-antigens. Here, we demonstrate the potential medicinal relevance of targeting the modification of tRNA in the treatment of a chronic multiple sclerosis model—murine experimental autoimmune encephalomyelitis. Administration of a de novo designed eukaryotic TGT substrate (NPPDAG) led to an unprecedented complete reversal of clinical symptoms and a dramatic reduction of markers associated with immune hyperactivation and neuronal damage after five daily doses. TGT is essential for the therapeutic effect, since animals deficient in TGT activity were refractory to therapy. The data suggest that exploitation of the eukaryotic TGT enzyme is a promising approach for the treatment of multiple sclerosis.
Queuine是一种仅来源于细菌的修饰吡咯并嘧啶核碱基。在几乎所有真核生物中，通过古老的tRNA鸟嘌呤转糖基酶（TGT）的活性，它在转录后取代了天冬氨酸、天冬酰胺、组氨酸和酪氨酸的同工受体tRNA中的鸟嘌呤34。用Queuine进行tRNA低修饰是快速增殖、未分化细胞的一个特征。包括多发性硬化症在内的自身免疫性疾病的特征是针对自身抗原的T细胞快速扩增。在此，我们证明了在慢性多发性硬化症模型——小鼠实验性自身免疫性脑脊髓炎的治疗中，靶向tRNA修饰的潜在医学相关性。给予一种从头设计的真核TGT底物（NPPDAG），在每日给药五次后，导致临床症状出现前所未有的完全逆转，并显著降低了与免疫过度激活和神经元损伤相关的标志物。TGT对治疗效果至关重要，因为缺乏TGT活性的动物对治疗无反应。数据表明，利用真核TGT酶是治疗多发性硬化症的一种有前景的方法。
