Epitomic Profiling and Functional Characteristics of Pemphigus Vulgaris Autoantibody Binding to Keratinocyte M3 Muscarinic Acetylcholine Receptor.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jorge Mauricio Reyes-Ruiz, Alex Chernyavsky, Sergei A Grando, Charles Glabe
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Abstract

Patients with pemphigus vulgaris (PV) develop IgG autoantibodies (AuAbs) binding to keratinocyte desmogleins (Dsg), acetylcholine (ACh) receptors, mitochondrial proteins, and some other self-antigens. In this study, we identified linear and discontinuous peptide tetrameric epitope segments (ES) of M3 muscarinic ACh receptor (M3AR) targeted by different anti-M3AR AuAbs. As positive controls, we identified Dsg1 and Dsg3 ES targeted by PV sera. Healthy individuals also possessed natural antibodies targeting M3AR, Dsg1 and Dsg3 epitopes that were different from those targeted by AuAbs produced by PV patients. The two targeted M3AR pentameric ES encompass the 10 amino acids-long epitope LSEPTITFGT included the tetramer TFGT containing Thr235 which is a part of the ACh-binding pocket. Previously, it has been demonstrated that the anti-M3AR AuAb produces an agonist-like effect on downstream signaling, but its long-term effect is receptor desensitization. In this study, we compared the functional consequences of binding anti-M3AR AuAbs that target the ACh-binding pocket with that of AuAbs that target M3AR outside of its ACh-binding pocket. While the former AuAbs induced a very high elevation of phospholipase C, inositol triphosphate and diacylglycerol, which represents an agonist-like effect, the latter AuAbs produced a much weaker signaling response. These results indicate that PV patients develop two types of anti-M3AR AuAbs. One type attaches to orthosteric, ie, ACh-binding, site and elicits a strong signaling response comparable to that induced by a full pharmacologic agonist, whereas another type binds to an allosteric site and elicits submaximal signaling response comparable to that induced by a partial (allosteric) agonist.

寻常型天疱疮自身抗体结合角质细胞M3毒蕈碱乙酰胆碱受体的表位特征及功能特征。
寻常型天疱疮(PV)患者会产生IgG自身抗体(AuAbs),该抗体与角化细胞粘粒蛋白(Dsg)、乙酰胆碱(ACh)受体、线粒体蛋白和其他一些自身抗原结合。在本研究中,我们鉴定了不同抗M3AR抗体靶向M3毒蕈碱ACh受体(M3AR)的线性和不连续肽四聚体表位片段(ES)。作为阳性对照,我们鉴定出PV血清靶向的Dsg1和Dsg3 ES。健康个体也具有针对M3AR、Dsg1和Dsg3表位的天然抗体,这些抗体与PV患者产生的AuAbs靶向的抗体不同。两个靶向M3AR五聚体ES包含10个氨基酸长的表位LSEPTITFGT包括含有Thr235的四聚体TFGT,这是ach结合口袋的一部分。之前已经证明抗m3ar AuAb对下游信号产生激动剂样作用,但其长期作用是受体脱敏。在这项研究中,我们比较了靶向ach结合袋的抗M3AR AuAbs与靶向ach结合袋外的M3AR AuAbs的功能后果。前者能诱导磷脂酶C、肌醇三磷酸和二酰基甘油的高度升高,表现出类似激动剂的作用,而后者产生的信号反应要弱得多。这些结果表明PV患者产生两种类型的抗m3ar抗体。一种类型附着于正构位点,即乙酰胆碱结合位点,并引发与完全药物激动剂诱导的强烈信号反应,而另一种类型与变构位点结合,并引发与部分(变构)激动剂诱导的次极大信号反应。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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