Dataset Information

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

SUBMITTER: Faustino LC

PROVIDER: S-EPMC6179164 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Faustino Larissa C LC Lombardi Angela A Madrigal-Matute Julio J Owen Randall P RP Libutti Steven K SK Tomer Yaron Y

The Journal of clinical endocrinology and metabolism 20181001 10

<h4>Context</h4>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.<h4>Objective< ...[more]

PMID: 30113675

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Project description:Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C is essential for B-cell transformation and development of several B-cell lymphomas particularly those are generated in an immuno-compromised background. EBNA3C recruits ubiquitin-proteasome machinery for deregulating multiple cellular oncoproteins and tumor suppressor proteins. Although EBNA3C is found to be ubiquitinated at its N-terminal region and interacts with 20S proteasome, the viral protein is surprisingly stable in growing B-lymphocytes. EBNA3C can also circumvent autophagy-lysosomal mediated protein degradation and subsequent antigen presentation for T-cell recognition. Recently, we have shown that EBNA3C enhances autophagy, which serve as a prerequisite for B-cell survival particularly under growth deprivation conditions. We now demonstrate that proteasomal inhibition by MG132 induces EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-expression systems. Interestingly, MG132 treatment promotes degradation of two EBNA3 family oncoproteins-EBNA3A and EBNA3C, but not the viral tumor suppressor protein EBNA3B. EBNA3C degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked polyubiquitinated, colocalized with the autophagy-lysosomal fraction in the cytoplasm and participated within p62-LC3B complex, which facilitates autophagy-mediated degradation. We further show that the degradation signal is present at the first 50 residues of the N-terminal region of EBNA3C. Proteasomal inhibition reduces the colony formation ability of this important viral oncoprotein, induces apoptotic cell death and increases transcriptional activation of both latent and lytic gene expression which further promotes viral reactivation from EBV transformed B-lymphocytes. Altogether, this study offers rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV associated B-cell lymphomas, where EBNA3C is expressed.

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Dataset Information

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

Publications

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

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