Interferon-α triggers autoimmune thyroid diseases via lysosomal-dependent degradation of thyroglobulin

Larissa C. Faustino, Angela Lombardi, Julio Madrigal-Matute, Randall P. Owen, Steven K. Libutti, Yaron Tomer

Research output: Contribution to journalArticle

2 Citations (Scopus)

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-A (IFNa), a cytokine secreted during viral infections, has emerged as a key trigger of AITD. We have shown that IFNa upregulates TG transcription; however, how the upregulation of TG transcription by IFNa triggers AITD is still unknown. Objective: To evaluate how IFNa triggers AITD by testing its effects on TG processing. Design: We exposed human thyroid cells to IFNa and evaluated its effects on TG expression and processing. Results: Human thyroid cells exposed to INFa had increased levels of TG mRNA but reduced TG protein levels, indicating TG protein degradation. IFNa induced endoplasmic reticulum stress, but surprisingly, neither the use of chemical chaperones nor proteasome inhibitor prevented IFNainduced TG degradation. IFNa 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 IFNa-induced degradation of TG. Conclusion: We have shown in this study IFNa-induced lysosomal-dependent degradation of TG in human thyroid cells. Our findings suggest that during viral infections, local thyroidal IFNa production can lead to lysosomal TG degradation, releasing pathogenic TG peptides that can trigger AITD.

Original languageEnglish (US)
Pages (from-to)3678-3687
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume103
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Thyroglobulin
Thyroid Diseases
Interferons
Autoimmune Diseases
Degradation
Autophagy
Thyroid Gland
Virus Diseases
Transcription
Up-Regulation
Genes
Fluxes
Light
Hashimoto Disease
Proteasome Inhibitors
Endoplasmic Reticulum Stress
Graves Disease
Processing
Epigenomics
Proteolysis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Interferon-α triggers autoimmune thyroid diseases via lysosomal-dependent degradation of thyroglobulin. / Faustino, Larissa C.; Lombardi, Angela; Madrigal-Matute, Julio; Owen, Randall P.; Libutti, Steven K.; Tomer, Yaron.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 103, No. 10, 01.10.2018, p. 3678-3687.

Research output: Contribution to journalArticle

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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-A (IFNa), a cytokine secreted during viral infections, has emerged as a key trigger of AITD. We have shown that IFNa upregulates TG transcription; however, how the upregulation of TG transcription by IFNa triggers AITD is still unknown. Objective: To evaluate how IFNa triggers AITD by testing its effects on TG processing. Design: We exposed human thyroid cells to IFNa and evaluated its effects on TG expression and processing. Results: Human thyroid cells exposed to INFa had increased levels of TG mRNA but reduced TG protein levels, indicating TG protein degradation. IFNa induced endoplasmic reticulum stress, but surprisingly, neither the use of chemical chaperones nor proteasome inhibitor prevented IFNainduced TG degradation. IFNa 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 IFNa-induced degradation of TG. Conclusion: We have shown in this study IFNa-induced lysosomal-dependent degradation of TG in human thyroid cells. Our findings suggest that during viral infections, local thyroidal IFNa production can lead to lysosomal TG degradation, releasing pathogenic TG peptides that can trigger AITD.",
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