TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective

Endocrine Reviews
Basil Rapoport, Sandra M McLachlan

Abstract

The TSH receptor (TSHR) on the surface of thyrocytes is unique among the glycoprotein hormone receptors in comprising two subunits: an extracellular A-subunit, and a largely transmembrane and cytosolic B-subunit. Unlike its ligand TSH, whose subunits are encoded by two genes, the TSHR is expressed as a single polypeptide that subsequently undergoes intramolecular cleavage into disulfide-linked subunits. Cleavage is associated with removal of a C-peptide region, a mechanism similar in some respects to insulin cleavage into disulfide linked A- and B-subunits with loss of a C-peptide region. The potential pathophysiological importance of TSHR cleavage into A- and B-subunits is that some A-subunits are shed from the cell surface. Considerable experimental evidence supports the concept that A-subunit shedding in genetically susceptible individuals is a factor contributing to the induction and/or affinity maturation of pathogenic thyroid-stimulating autoantibodies, the direct cause of Graves' disease. The noncleaving gonadotropin receptors are not associated with autoantibodies that induce a "Graves' disease of the gonads." We also review herein current information on the location of the cleavage sites, the enzyme(s) responsible for ...Continue Reading

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Citations

Sep 8, 2016·Frontiers in Endocrinology·Hidefumi InabaTakashi Akamizu
Jan 28, 2017·Expert Opinion on Therapeutic Targets·Terry Smith
Jan 18, 2017·Cellular and Molecular Life Sciences : CMLS·Alexander WidiapradjaScott P Levick
Mar 30, 2017·Endocrine-related Cancer·Christopher W RoweRoger Smith
Jan 13, 2018·Frontiers in Immunology·Sandra M McLachlan, Basil Rapoport
Jan 29, 2019·Journal of Molecular Endocrinology·Jennifer Miller-GallacherBernard Rees Smith
Apr 5, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Sandra M McLachlanBasil Rapoport
Jun 12, 2019·Thyroid : Official Journal of the American Thyroid Association·Sandra M McLachlanBasil Rapoport
Jan 18, 2017·Frontiers in Endocrinology·Terry J Smith, Joseph A M J L Janssen
Jun 18, 2017·Frontiers in Immunology·Ralf J LudwigFalk Nimmerjahn
Sep 20, 2018·International Journal of Molecular Sciences·Marta ZąbczyńskaEwa Pocheć
May 26, 2017·Frontiers in Immunology·Eleonore Fröhlich, Richard Wahl
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