Lysosome-mediated aggregation of galactose-deficient IgA1 with transferrin receptor 1 links to IgA nephropathy

Meijun Si, Jingpeng Fu, Mengting Fang, Yunfei Lu, Junxuan Huang, Haojie Li, Peiyi Wang, Maofu Liao, Jian Zhu, Peiyao Li, Wenzhao Zhong, Zhifei Guo, Wei Yang, Zhiming Ye, Hongli Hu () and Xueqing Yu ()
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Meijun Si: Southern Medical University
Jingpeng Fu: The Chinese University of Hong Kong
Mengting Fang: Southern Medical University
Yunfei Lu: Southern Medical University
Junxuan Huang: Southern Medical University
Haojie Li: Southern Medical University
Peiyi Wang: Southern University of Science and Technology
Maofu Liao: Southern University of Science and Technology
Jian Zhu: Southern University of Science and Technology
Peiyao Li: Southern University of Science and Technology
Wenzhao Zhong: Southern Medical University
Zhifei Guo: Inc.
Wei Yang: Guangdong Academy of Medical Sciences
Zhiming Ye: Southern Medical University
Hongli Hu: The Chinese University of Hong Kong
Xueqing Yu: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The retention of galactose-deficient IgA1 (Gd-IgA1) in the mesangium is central to IgA nephropathy (IgAN), but its intracellular fate remains unclear. Here, we show that transferrin receptor 1 (TfR1) mediates Gd-IgA1 uptake into mesangial cell lysosomes, where it forms non-digestible aggregates, disrupts lysosomal function, and triggers inflammatory responses. In renal biopsies from IgAN patients, IgA1 aggregates co-localize with TfR1 within lysosomes. In male mice, TfR1 overexpression enhanced lysosomal accumulation of Gd-IgA1, whereas TfR1 knockdown reduced it. Mechanistically, acidic pH strengthens TfR1–Gd-IgA1 binding via the galactose-deficient hinge region and residue R276. While we acknowledge that sialylation commonly found in patient-derived IgA1 might influence TfR1 binding and that other receptors, such as ASGPR, were not evaluated, our findings nonetheless reveal a lysosome-centered mechanism in IgAN and highlight receptor-mediated retention of Gd-IgA1 as a potential therapeutic target.

Date: 2025
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DOI: 10.1038/s41467-025-60819-w

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