The antigen-binding fragment of anti-double-stranded DNA IgG enhances F-actin formation in mesangial cells by binding to alpha-actinin-4

Author:

Zou Xiaoyan12,Cheng Hong1,Zhang Yi13,Fang Chunhong4,Xia Yumin4

Affiliation:

1. Department of Medicine, Renmin Hospital of Wuhan University, Wuhan 430060

2. Department of Dermatology, Hubei Maternity and Child Health Hospital, Wuhan 430070

3. Department of Medicine, Gezhouba Central Hospital, The Third Clinical Hospital of Three Gorges University, Yichang 443002

4. Department of Dermatology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, China

Abstract

Anti-double-stranded DNA (dsDNA) IgG causes renal damage in patients with lupus nephritis by cross-reacting with multiple autoantigens, including alpha-actinin-4, in mesangial cells (MCs). However, how the cross-reactions play a role in mesangial phenotypic abnormalities is not well understood. Here, we investigated the effects of the fragment antigen-binding (Fab) of anti-dsDNA IgG3 on the biochemical properties of alpha-actinin-4. Experiments revealed that anti-dsDNA Fab specifically binds to alpha-actinin-4, but not G-actin. The binding by anti-dsDNA Fab sequentially increases the positive charge of alpha-actinin-4 and inhibits the affinity of alpha-actinin-4 to calcium ions. By the low shear viscosity and a co-sedimentation assay, we found that the alpha-actinin-4-induced F-actin gelation improves when anti-dsDNA Fab is added. However, the Fab control has no such effect on F-actin gelation. Furthermore, the in vitro cultured MCs exhibit higher F-actin expression and transforming growth factor- β1 synthesis after the incubation with anti-dsDNA Fab. Therefore, our results indicated that anti-dsDNA Fab may enhance F-actin formation by the proprietary modification of alpha-actinin-4, which could partially explain the myofibroblast-like phenotype of MCs in anti-dsDNA-positive lupus nephritis.

Publisher

SAGE Publications

Subject

General Biochemistry, Genetics and Molecular Biology

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