SEC24C调控内质网自噬介导的C1GALT1降解参与IgA肾病的作用和机制

IgA肾病（IgAN）是最常见的原发性肾小球疾病。C1GALT1低表达是IgAN发生发展的关键，但其具体调控机制不明。既往研究证实内质网稳态失衡导致蛋白异常折叠并通过自噬等途径降解，SEC24C在维持内质网稳态中起重要作用。我们前期预实验发现：SEC24C在IgAN病人外周血B细胞中低表达；抑制B细胞中SEC24C表达诱导内质网稳态失衡、C1GALT1折叠异常和降解并激活内质网自噬。由此推测SEC24C低表达诱导内质网自噬介导C1GALT1降解是IgAN发生的关键。本项目将利用不同病理类型及疾病阶段的IgAN患者外周血B细胞、分泌IgA的人B淋巴细胞株和IgAN小鼠模型，采用抑制/过表达SEC24C、免疫电镜、激光共聚焦等方法明确SEC24C调节内质网自噬介导C1GALT1降解在IgAN发生发展中的作用及分子机制。本研究旨在揭示IgAN发病新机制，为IgAN防治提供新的理论依据与治疗靶点。

IgA nephropathy (IgAN) is the most common primary glomerular disease. Reduced expression of C1GALT1 contributes critically to the development of IgAN. However, the underlying mechanism for the reduction of C1GALT1 remains largely unclear. Previous studies have revealed that loss of endoplasmic reticulum (ER) homeostasis induces protein misfolding and subsequent protein degradation through pathways such as autophagy, and SEC24C plays a critical role in maintaining ER homeostasis. Our preliminary work suggested that SEC24C was downregulated in peripheral B cells of IgAN patients compared to healthy controls, and suppression of SEC24C expression in B cells led to the loss of ER homeostasis, C1GALT1 misfolding and degradation and activation of ER-phagy. Therefore, we propose that the reduction of SEC24C stimulates ER-phagy related C1GALT1 degradation contributes critically to the development and progress of IgAN. In this project, peripheral blood B cells of IgAN patients with different pathological types and disease stages, IgA-secreting human B lymphocyte strains and IgAN mouse models will be used. It aims to further verify the role and mechanism of SEC24C involved in regulating ER-phagy-mediated C1GALT1 degradation in IgAN through immunoelectron microscopy, confocal microscopy and other methods. The present study will not only gain an in-depth understanding of the mechanism of IgAN development but also provide new targets for intervention in IgAN.