Interferon-α Triggers Autoimmune Thyroid Diseases via Lysosomal-Dependent Degradation of Thyroglobulin.

Abstract

Context:

Autoimmune thyroid diseases (AITDs) arise from complex interactions among genetic, epigenetic, and environmental factors. Thyroglobulin (TG) is a major susceptibility gene for both Graves disease and Hashimoto thyroiditis. Interferon-α (IFNα), a cytokine secreted during viral infections, has emerged as a key trigger of AITD. We have shown that IFNα upregulates TG transcription; however, how the upregulation of TG transcription by IFNα triggers AITD is still unknown.

Objective:

To evaluate how IFNα triggers AITD by testing its effects on TG processing.

Design:

We exposed human thyroid cells to IFNα and evaluated its effects on TG expression and processing.

Results:

Human thyroid cells exposed to INFα had increased levels of TG mRNA but reduced TG protein levels, indicating TG protein degradation. IFNα induced endoplasmic reticulum stress, but surprisingly, neither the use of chemical chaperones nor proteasome inhibitor prevented IFNα-induced TG degradation. IFNα also increased LysoTracker staining and autophagy flux measured by net light chain 3 (LC3)-II and p62 fluxes. In addition, expression of autophagy markers LC3 and autophagy-related gene 5 was higher in thyroid tissues from patients with AITD. Finally, blocking lysosomal degradation prevented IFNα-induced degradation of TG.

Conclusion:

We have shown in this study IFNα-induced lysosomal-dependent degradation of TG in human thyroid cells. Our findings suggest that during viral infections, local thyroidal IFNα production can lead to lysosomal TG degradation, releasing pathogenic TG peptides that can trigger AITD.

• Authors: Larissa C Faustino, Angela Lombardi, Julio Madrigal-Matute, Randall P Owen, Steven K Libutti, Yaron Tomer
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 103 Issue 10 Pg. 3678-3687 (10 01 2018) ISSN: 1945-7197 [Electronic] United States
• PMID: 30113675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Interferon-alpha
• Thyroglobulin

Topics

• Antiviral Agents (adverse effects)
• Autoimmune Diseases (chemically induced, metabolism, pathology)
• Autophagy
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Interferon-alpha (adverse effects)
• Lysosomes (metabolism)
• Proteolysis
• Thyroglobulin (genetics, metabolism)
• Thyroid Diseases (chemically induced, metabolism, pathology)