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

5 Scopus citations

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

ASJC Scopus subject areas

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

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