Englebienne, P., Verhas, M., Herst, C. and K. De Meirleir. 2003. Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasomes: possible etiology for unexplained chronic fatigue. Medical Hypotheses 60, 175-180.
This article is unbelievably complex; hopefully this synopsis is correct on the basic points.
CFS patients are biochemically euthyroid (normal thyroid function) but the severe fatigue they present clinically suggests they are hypothyroid (low thyroid). CFS patients also suffer from a dysregulated part of the immune system (Interferon) which can result in severe fatigue. In this article the authors propose that the severe fatigue seen in CFS patients, and in patients with cancer, hepatitis and MS undergoing IFN a/b treatments, is caused by an IFN induced repression or destruction of the thyroid receptors (TR’s). Since the inhibition of TR activity levels does not effect thyroid hormone production this presents a scenario in which patients appear biochemically euthyroid but are clinically hypothyroid; i.e. the signal is there – its just not getting through.
The genesis of this problem occurs during the induction of 2-5OAS-like proteins (p30, p56/p59) called 2-5OASL by type I IFN’s (IFN a/b). These protein were discovered in 1995 but their function remains unknown. (An examination of the catalytic regions of the 2-5OAS and 2-5OASL proteins revealed subtle differences that probably account for 2-5OASL’s inability to act like 2-5OAS; i.e. to cut up ATP and form 2-5A). A ‘BLAST’ search of the NCBI database indicated that the 2-5OASL proteins share a 96% homology with a thyroid interacting protein (TRIP) – TRIP 14. (Interestingly this protein only interacts with proteins in cells grown without thyroid hormone (?)).
In the cell the thyroid receptor is typically bound to another receptor – the retinoid x receptor. Proteins are able to activate or repress thyroid receptor activity by binding to the binding domains found on both of these receptors. Thus two binding domains need to be filled to effect thyroid receptor activity. While the 2-5OASL proteins contain the motif needed to interact with these binding domains they appeared to only have one of them. A further amino acid scan identified, however, another motif (SCAN) which appears to be able to bind with the other. Thus the p30 and p56/59 OASL proteins appear to be able to engage with and repress thyroid receptor functioning.
An ‘e-motif’ search of the amino acid domains of the OASL proteins revealed the presence of motifs on the p56/50 OASL’s that interact with ubiquitin proteins. Ubiquitins target proteins for destruction by (26S) proteasomes. The ubiquitin system of protein degradation plays an important role in the regulation of the cell cycle, signal transduction, gene transcription and endocytosis. (Endocytosis is the incorporation of an extracellular substance into a cell such as when dendritic cells, macrophages and phagocytes ingest all or parts of invaders.) This suggests that after binding to thyroid receptors the p56/59 OASL proteins could target them for destruction with their ubiquitin motifs.
Conclusion: the authors propose that the fatigue seen in CFS and in those patients given IFN A/B treatments is caused when increased IFN a/b activity causes the 2-5OASL proteins to either repress thyroid receptor activity (p30 or p56/59) or target the TR’s (p56/p59) for destruction by proteasomes. Since the signal from the thyroid hormone is unable get through to the cells nucleus these patients remain biochemically euthryoid but clinically hypothyroid.
(One wonders why the body would have IFN target the thyroid receptor? What positive function could this serve? Perhaps the fatigue generated is an important part of the body telling itself to rest?)
(Funding for CFS is at atrociously low levels. Because, however, diseases with proper funding get money not only for treatment but on the remittance of symptoms sometimes caused by treatments perhaps this paper will prompt cancer, hepatitis or MS researchers to further explore the intricacies of the IFN/2-5OASL system. Perhaps unwittingly they will stumble upon some information of interest for CFS patients.)