Gismene Carolina, de Moraes Fábio Rogério, Bauermeister Anelize, Santana Da Costa Thyerre, Calmon Marilia de Freitas, Cerbino Luís Eduardo de Almeida Passos, Rahal Paula, Maira Góes Rejane, de Moraes Luiz Alberto Beraldo, Tasic Ljubica, Arni Raghuvir Krishnaswamy
Multiuser Center for Biomolecular Innovation, São Paulo State University - UNESP, São José do Rio Preto, SP 15054-000, Brazil.
Department of Chemistry, Institute of Chemistry, University of São Paulo - USP, São Paulo, SP 05508-000, Brazil.
J Proteome Res. 2025 Jul 4;24(7):3261-3271. doi: 10.1021/acs.jproteome.4c01029. Epub 2025 May 22.
Exfoliative toxins (ETs) are glutamyl endopeptidases (GEPs) belonging to the chymotrypsin-like serine protease family (CLSPs), and they play crucial roles in diverse skin diseases. Specifically, exfoliative toxin C (ExhC), expressed by , is an atypical CLSP and has been classified as a moonlighting protein due to its ability to induce necrosis in specific cell lines, inhibit the phagocytic activity of macrophages, and cause skin exfoliation in pigs and mice. The latter function is attributed to the high specificity of ExhC for porcine and murine desmoglein-1, a cadherin that contributes to cell-cell adhesion within the epidermis. Although the amino acid residues responsible for ExhC-induced necrosis have been identified, the specific cellular metabolic pathways leading to cell death remain unclear. Herein, we employed nuclear magnetic resonance (NMR) and mass spectrometry (MS) to explore the metabolic pathways affected by the necrotic activity of ExhC in the BHK-21 cell line. The metabolic profile of cells exposed to subtoxic doses of ExhC revealed significant alterations in oxidative stress protection, energy production, and gene expression pathways. The data demonstrate the potential mechanisms of action of ExhC and highlight that this toxin causes cellular damage, even at low concentrations.
剥脱毒素（ETs）是属于胰凝乳蛋白酶样丝氨酸蛋白酶家族（CLSPs）的谷氨酰内肽酶（GEPs），它们在多种皮肤疾病中发挥关键作用。具体而言，由[具体表达源未给出]表达的剥脱毒素C（ExhC）是一种非典型的CLSP，由于其能够在特定细胞系中诱导坏死、抑制巨噬细胞的吞噬活性以及在猪和小鼠中引起皮肤剥脱，已被归类为一种兼职蛋白。后一种功能归因于ExhC对猪和鼠桥粒芯糖蛋白-1的高特异性，桥粒芯糖蛋白-1是一种有助于表皮内细胞间粘附的钙粘蛋白。尽管已经确定了导致ExhC诱导坏死的氨基酸残基，但导致细胞死亡的具体细胞代谢途径仍不清楚。在此，我们利用核磁共振（NMR）和质谱（MS）来探索ExhC在BHK-21细胞系中的坏死活性所影响的代谢途径。暴露于亚毒性剂量ExhC的细胞的代谢谱显示，氧化应激保护、能量产生和基因表达途径发生了显著变化。这些数据证明了ExhC的潜在作用机制，并突出表明即使在低浓度下，这种毒素也会导致细胞损伤。
