GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles
Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced "on-demand" GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.
Authors
- Yanwu Guo (ORCID: https://orcid.org/0000-0002-2368-4375)
- Wen‐Jun Xin (ORCID: https://orcid.org/0000-0002-5380-8738)
- Meiqiu Liu
- Jianping Zhu (ORCID: https://orcid.org/0000-0001-5160-6991)
- Wangming Zhang (ORCID: https://orcid.org/0000-0003-4506-6321)
- Zhenhai Zhang (ORCID: https://orcid.org/0000-0002-4310-0525)
- Rongqing Chen (ORCID: https://orcid.org/0000-0002-1668-8554)
- Xiangzhen Tong
- Su‐Yan Lin (ORCID: https://orcid.org/0000-0003-1769-2683)
- Weiyuan Huang (ORCID: https://orcid.org/0000-0002-8062-0255)
- Mei Liu (ORCID: https://orcid.org/0000-0003-0851-3858)
- Yue Ke
- Mei Li (ORCID: https://orcid.org/0000-0002-2544-5618)
- Jiawei Zheng (ORCID: https://orcid.org/0000-0002-5381-2729)
- Zhi‐Peng Guo (ORCID: https://orcid.org/0000-0001-8193-6086)
- Lijuan Jiang (ORCID: https://orcid.org/0000-0003-2654-7920)
- Cong Jin (ORCID: https://orcid.org/0009-0008-9628-0719)
- Xing‐Mei Zhang (ORCID: https://orcid.org/0000-0002-8728-8849)
- Xuan Han
- Shuang Zhu (ORCID: https://orcid.org/0000-0002-5181-4181)
Institutions
- Sun Yat-sen University (CN)
- Ministry of Education (RW)
- Zhujiang Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-02-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.115343
- Citations
- 13
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 14.53
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- Guangdong Science and Technology Department