title: Tissue transglutaminase contributes to the pathogenesis of preeclampsia and stabilizes placental angiotensin receptor type 1 by ubiquitination-preventing isopeptide modification.
abstract: Preeclampsia is a life-threatening pregnancy disorder that is widely thought to be triggered by impaired placental development. However, the placenta-related pathogenic factors are not fully identified, and their underlying mechanisms in disease development remain unclear. Here, we report that the protein level and enzyme activity of tissue transglutaminase (TG2 or tTG), the most ubiquitous member of a family of enzymes that conducts post-translational modification of proteins by forming ε-(γ-glutamyl)-lysine isopeptide bonds, are significantly elevated in placentas of preeclamptic women. TG2 is localized in the placental syncytiotrophoblasts of patients with preeclampsia where it catalyzes the isopeptide modification of the angiotensin receptor type 1 (AT1). To determine the role of elevated TG2 in preeclampsia, we used a mouse model of preeclampsia based on injection of AT1-agonistic autoantibody. A pathogenic role for TG2 in preeclampsia is suggested by in vivo experiments in which cystamine, a potent transglutaminase inhibitor, or small interfering RNA-mediated TG2 knockdown significantly attenuated autoantibody-induced hypertension and proteinuria in pregnant mice. Cystamine treatment also prevented isopeptide modification of placental AT1 receptors in preeclamptic mice. Mechanistically, we revealed that AT1-agonistic autoantibody stimulation enhances the interaction between AT1 receptor and TG2 and results in increased AT1 receptor stabilization via transglutaminase-mediated isopeptide modification in trophoblasts. Mutagenesis studies further demonstrated that TG2-mediated isopeptide modification of AT1 receptors prevents ubiquitination-dependent receptor degradation. Taken together, our studies not only identify a novel pathogenic involvement of TG2 in preeclampsia but also suggest a previously unrecognized role of TG2 in the regulation of G protein-coupled receptor stabilization by inhibiting ubiquitination-dependent degradation.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas. Yang.Xia@uth.tmc.edu or Rodney.E.Kellems@uth.tmc.edu.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Parchim
authors.forename: Roxanna A
authors.initials: RA
authors.lastname: Irani
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.forename: Baha
authors.initials: B
authors.lastname: Sibai
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D002460:Cell Line; D004151:Dipeptides / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011499:Protein Processing, Post-Translational / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: D004151:Dipeptides; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; C001299:epsilon-(gamma-glutamyl)-lysine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: angiotensin AT1 receptor; preeclampsia; pregnancy; protein processing, post-translational; renin–angiotensin system; transglutaminase 2; ubiquitination