title: Withdrawn: TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective.
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 lossofaC-peptideregion. 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 cleavage, the mechanism by which A-subunits are shed, and the effects of cleavage on receptor signaling. (Endocrine Reviews 37: 114-134, 2016).
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California 90048.
authors.forename: Basil
authors.initials: B
authors.lastname: Rapoport
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California 90048.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: McLachlan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D006111:Graves Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011499:Protein Processing, Post-Translational; D011989:Receptors, Thyrotropin / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D000072637:Thyroid Epithelial Cells / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D011989:Receptors, Thyrotropin