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.
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.
Englebienne
P
P
University of Brussels (ULB/VUB), N.V., Brussels, Belgium. penglebi@ulb.ac.be
Verhas
M
M
Herst
C V
CV
De Meirleir
K
K
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
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