Research ArticleAutoimmunity

Biased signaling by thyroid-stimulating hormone receptor–specific antibodies determines thyrocyte survival in autoimmunity

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Sci. Signal.  23 Jan 2018:
Vol. 11, Issue 514, eaah4120
DOI: 10.1126/scisignal.aah4120

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Antibodies determine thyrocyte fate

Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism and the presence of autoantibodies against the thyroid-stimulating hormone receptor (TSHR), which are classified as stimulatory, blocking, or neutral and which bind to different receptor epitopes. Binding of TSH to the TSHR, a member of the GPCR superfamily, leads to the activation of G proteins and, in response to receptor phosphorylation, the activation of β-arrestin–dependent signaling. Through imaging analysis, Morshed et al. showed that exposure of thyrocytes to the stimulatory antibody S-TSHR-Ab led to G protein signaling, receptor internalization, and endosomal formation. In contrast, a neutral antibody (C-TSHR-Ab) induced β-arrestin–dependent signaling, but not G protein–dependent signaling, had defective trafficking, and accumulated intracellularly. This, in turn, triggered thyrocyte death by apoptosis. Together, these data suggest a mechanism by which different autoantibodies differentially affect thyrocyte homeostasis, which may have implications for the treatment of GD.


The thyroid-stimulating hormone receptor (TSHR) is a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor (GPCR). Autoimmune hyperthyroidism, commonly known as Graves’ disease (GD), is caused by stimulating autoantibodies to the TSHR. We previously described TSHR-specific antibodies (TSHR-Abs) in GD that recognize linear epitopes in the cleavage region of the TSHR ectodomain (C-TSHR-Abs) and induce thyroid cell apoptosis instead of stimulating the TSHR. We found that C-TSHR-Abs entered the cell through clathrin-mediated endocytosis but did not trigger endosomal maturation and failed to undergo normal vesicular sorting and trafficking. We found that stimulating TSHR-Abs (S-TSHR-Abs) activated Gαs and, to a lesser extent, Gαq but that C-TSHR-Abs failed to activate any of the G proteins normally activated in response to TSH. Furthermore, specific inhibition of G proteins in the presence of S-TSHR-mAbs or TSH resulted in a similar failure of endosomal maturation as that caused by C-TSHR-mAbs. Hence, whereas S-TSHR-mAbs and TSH contributed to normal vesicular trafficking of TSHR through the activation of major G proteins, the C-TSHR-Abs resulted in GRK2- and β-arrestin-1–dependent biased signaling, which is interpreted as a danger signal by the cell. Our observations suggest that the binding of antibodies to different TSHR epitopes may decrease cell survival. Antibody-induced cell injury and the response to cell death amplify the loss of self-tolerance, which most likely helps to perpetuate GPCR-mediated autoimmunity.

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