A novel mutation of indoleamine 2,3-dioxygenase 1 causes a rapid proteasomal degradation and compromises protein function

• Published in: Journal of autoimmunity Vol. 115; p. 102509
• Main Authors: Mondanelli, Giada, Di Battista, Valeria, Pellanera, Fabrizia, Mammoli, Andrea, Macchiarulo, Antonio, Gargaro, Marco, Mavridou, Elena, Matteucci, Caterina, Ruggeri, Loredana, Orabona, Ciriana, Volpi, Claudia, Grohmann, Ursula, Mecucci, Cristina
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2020
• Subjects: Autoimmune diseases; Indoleamine 2,3-dioxygenase 1 (IDO1); Missense mutation; Proteasomal degradation; Tryptophan catabolism; Proteasomal degradation; Missense mutation; Tryptophan catabolism; Autoimmune diseases; Indoleamine 2,3-dioxygenase 1 (IDO1)
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2020.102509

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. •Indoleamine 2,3-dioxygenase 1 (IDO1) enzyme controls immune responses.•Accelerated proteasomal degradation of IDO1 lays the ground for autoimmunity.•Missense mutation at IDO1 exon 9 is associated with impaired immune tolerance.•Mutated IDO1 protein undergoes an accelerated protein turnover.•IDO1 functional mutations could be exploited to personalize immunotherapy.