title: Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasome: possible etiology for unexplained chronic fatigue.
abstract: In some patients complaining of chronic fatigue such as those suffering from the chronic fatigue syndrome (CFS), no underlying physical cause can be clearly identified and they typically present a normal thyroid function. Several studies indicate a dysregulation in the type I interferons (IFN-alpha/beta) pathway in CFS resulting in a sustained upregulation of 2('),5(')-oligoadenylate synthetases (2-5OAS). Likewise, patients treated with IFN-alpha/beta usually complain of severe fatigue as a limiting side effect. Beside the 2-5OAS, IFN-alpha/beta induce also the expression of three closely related proteins of unknown function termed the 2-5OAS-like (2-5OASL) proteins. The amino acid sequences of the 2-5OASL proteins display 96% identity with the partial sequence of the thyroid receptor interacting protein (TRIP) 14, further contain two typical thyroid hormone receptor (TR) coregulator domains and feature two ubiquitin C-terminal domains. From these observations, we raise the hypothesis that the 2-5OASL proteins are TRIPs capable of, respectively, repressing TR transactivation and/or signaling the receptor for destruction by the proteasome. Such molecular mechanisms could explain the development of a clinical hypothyroid state in presence of a normal thyroid function.
authors.affiliation: University of Brussels (ULB/VUB), N.V., Brussels, Belgium. penglebi@ulb.ac.be
authors.forename: P
authors.initials: P
authors.lastname: Englebienne
authors.forename: M
authors.initials: M
authors.lastname: Verhas
authors.forename: C V
authors.initials: CV
authors.lastname: Herst
authors.forename: K
authors.initials: K
authors.lastname: De Meirleir
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015673:Fatigue Syndrome, Chronic / Q000209:etiology*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D007370:Interferon Type I; D009097:Multienzyme Complexes; D011988:Receptors, Thyroid Hormone; C115020:OASL protein, human; D015088:2',5'-Oligoadenylate Synthetase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex