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A novel mutation of indoleamine 2,3-dioxygenase 1 causes a rapid proteasomal degradation and compromises protein function.
Journal of Autoimmunity ( IF 12.8 ) Pub Date : 2020-06-27 , DOI: 10.1016/j.jaut.2020.102509
Giada Mondanelli 1 , Valeria Di Battista 2 , Fabrizia Pellanera 2 , Andrea Mammoli 3 , Antonio Macchiarulo 3 , Marco Gargaro 1 , Elena Mavridou 2 , Caterina Matteucci 2 , Loredana Ruggeri 2 , Ciriana Orabona 1 , Claudia Volpi 1 , Ursula Grohmann 1 , Cristina Mecucci 2
Affiliation  

Indoleamine 2,3-dioxygenase 1 (IDO1) – the enzyme catalyzing the rate-limiting step of tryptophan catabolism along the kynurenine pathway – belongs to the class of inhibitory immune checkpoint molecules. Such regulators of the immune system are crucial for maintaining self-tolerance and thus, when properly working, preventing autoimmunity. A dysfunctional IDO1 has recently been associated with a specific single nucleotide polymorphism (SNP) and with the occurrence of autoimmune diabetes and multiple sclerosis. Many genetic alterations of IDO1 have been proposed being related with dysimmune disorders. However, the molecular and functional meaning of variations in IDO1 exomes as well as the promoter region remains a poorly explored field. In the present study, we identified a rare missense variant (rs751360195) at the IDO1 gene in a patient affected by coeliac disease, thyroiditis, and selective immunoglobulin A deficiency. Molecular and functional studies demonstrated that the substitution of lysine (K) at position 257 with a glutamic acid (E) results in an altered IDO1 protein that undergoes a rapid protein turnover. This genotype-to-phenotype relation is produced by peripheral blood mononuclear cells (PBMCs) of the patient bearing this variation and is associated with a specific phenotype (i.e., impaired tryptophan catabolism and defective mechanisms of immune tolerance). Thus decoding functional mutations of the IDO1 exome may provide clinically relevant information exploitable to personalize therapeutic interventions.



中文翻译:

吲哚胺 2,3-双加氧酶 1 的新突变导致蛋白酶体快速降解并损害蛋白质功能。

吲哚胺 2,3-双加氧酶 1 (IDO1) - 催化犬尿氨酸途径中色氨酸分解代谢的限速步骤的酶 - 属于抑制性免疫检查点分子类别。免疫系统的此类调节剂对于维持自身耐受性至关重要,因此,在正常工作时,可以防止自身免疫。最近发现功能失调的 IDO1 与特定的单核苷酸多态性 (SNP) 以及自身免疫性糖尿病和多发性硬化症的发生有关。已经提出 IDO1 的许多基因改变与免疫失调有关。然而,IDO1 外显子组和启动子区域变异的分子和功能意义仍然是一个探索不足的领域。在本研究中,我们在IDO1患有乳糜泻、甲状腺炎和选择性免疫球蛋白 A 缺乏症的患者中的基因。分子和功能研究表明,用谷氨酸 (E) 替换第 257 位的赖氨酸 (K) 会导致 IDO1 蛋白发生改变,该蛋白经历快速蛋白质周转。这种基因型与表型的关系是由携带这种变异的患者的外周血单核细胞 (PBMC) 产生的,并且与特定的表型有关(即,色氨酸分解代谢受损和免疫耐受机制有缺陷)。因此,解码 IDO1 外显子组的功能突变可能会提供可用于个性化治疗干预的临床相关信息。

更新日期:2020-06-27
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