RhoA vesicle trafficking-mediated transglutaminase 2 membrane translocation promotes IgA1 mesangial deposition in IgA nephropathy.
RhoA vesicle trafficking-mediated transglutaminase 2 membrane translocation promotes IgA1 mesangial deposition in IgA nephropathy.
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DOI：
10.1172/jci.insight.160374
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发表时间：
2023-10-09
期刊：
影响因子：
8
通讯作者：
Feng, Shaozhen
中科院分区：
文献类型：
--
作者：
Zhong, Zhong;Li, Zhijian;Li, Yanjie;Jiang, Lanping;Kong, Qingyu;Chen, Wei;Feng, Shaozhen
在伊加肾病（IgAN）的人源化小鼠模型中，转氨酶2（TGase2）已被证明有助于系膜IgA 1沉积，但其机制尚不完全清楚。在这项研究中，我们发现，抑制TGase2的活性可以显着减少从IgAN患者中分离的与人系膜细胞（HMC）相互作用的多聚IgA 1（pIgA 1）的量。TGase2在HMC胞浆和胞膜上均有表达。用pIgA1处理后，有更多的TGase2募集到膜上。使用pIgA1的系膜沉积的细胞模型，我们确定了253个潜在的TGase2相关蛋白质的胞浆部分，并观察到更高浓度的细胞囊泡和Ras同源家族成员A（RhoA）在HMC中的表达增加后，pIgA1刺激。通过抑制囊泡运输途径，HMC上的pIgA 1沉积量和膜TGase 2水平均降低。从机制上讲，TGase2被发现与RhoA在细胞囊泡中共沉淀。膜TGase2的表达大大增加了RhoA的过度表达，而RhoA的敲低则降低。我们的体外方法表明，TGase2从胞质溶胶运输到膜通过RhoA介导的囊泡运输途径，可以促进pIgA1与IgAN系膜的相互作用。
Transglutaminase 2 (TGase2) has been shown to contribute to the mesangial IgA1 deposition in a humanized mouse model of IgA nephropathy (IgAN), but the mechanism is not fully understood. In this study, we found that inhibition of TGase2 activity could dramatically decrease the amount of polymeric IgA1 (pIgA1) isolated from patients with IgAN that interacts with human mesangial cells (HMC). TGase2 was expressed both in the cytosol and on the membrane of HMC. Upon treatment with pIgA1, there were more TGase2 recruited to the membrane. Using a cell model of mesangial deposition of pIgA1, we identified 253 potential TGase2-associated proteins in the cytosolic fraction and observed a higher concentration of cellular vesicles and increased expression of Ras homolog family member A (RhoA) in HMC after pIgA1 stimulation. Both the amount of pIgA1 deposited on HMC and membrane TGase2 level were decreased by inhibition of the vesicle trafficking pathway. Mechanistically, TGase2 was found to be coprecipitated with RhoA in the cellular vesicles. Membrane TGase2 expression was greatly increased by overexpression of RhoA, while it was reduced by knockdown of RhoA. Our in vitro approach demonstrated that TGase2 was transported from the cytosol to the membrane through a RhoA-mediated vesicle-trafficking pathway that can facilitate pIgA1 interaction with mesangium in IgAN.
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