2. Academic Validation
  3. GPNMB disrupts SNARE complex assembly to maintain bacterial proliferation within macrophages

GPNMB disrupts SNARE complex assembly to maintain bacterial proliferation within macrophages

  • Cell Mol Immunol. 2025 Mar 4. doi: 10.1038/s41423-025-01272-z.
Zhenzhen Yan 1 2 3,  Jinghong Han 1 2,  Zihao Mi 1 2,  Zhenzhen Wang 1 2,  Yixuan Fu 3,  Chuan Wang 1 2,  Ningning Dang 3,  Hong Liu 4 5 6,  Furen Zhang 7 8 9
Affiliations

Affiliations

  • 1 Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.
  • 2 Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 3 Department of Dermatology, Shandong Provincial Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China.
  • 4 Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China. hongyue2519@hotmail.com.
  • 5 Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China. hongyue2519@hotmail.com.
  • 6 School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. hongyue2519@hotmail.com.
  • 7 Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China. zhangfuren@hotmail.com.
  • 8 Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China. zhangfuren@hotmail.com.
  • 9 School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. zhangfuren@hotmail.com.
PMID: 40038549 DOI: 10.1038/s41423-025-01272-z
Abstract

Xenophagy plays a crucial role in restraining the growth of intracellular bacteria in macrophages. However, the machinery governing autophagosome‒lysosome fusion during Bacterial infection remains incompletely understood. Here, we utilize leprosy, an ideal model for exploring the interactions between host defense mechanisms and Bacterial infection. We highlight the glycoprotein nonmetastatic melanoma protein B (GPNMB), which is highly expressed in macrophages from lepromatous leprosy (L-Lep) patients and interferes with xenophagy during Bacterial infection. Upon Infection, GPNMB interacts with autophagosomal-localized STX17, leading to a reduced N-glycosylation level at N296 of GPNMB. This modification promotes the degradation of SNAP29, thus preventing the assembly of the STX17-SNAP29-VAMP8 SNARE complex. Consequently, the fusion of autophagosomes with lysosomes is disrupted, resulting in inhibited cellular autophagic flux. In addition to Mycobacterium leprae, GPNMB deficiency impairs the proliferation of various intracellular bacteria in human macrophages, suggesting a universal role of GPNMB in intracellular Bacterial infection. Furthermore, compared with their counterparts, Gpnmbfl/fl Lyz2-Cre mice presented decreased Mycobacterium marinum amplification. Overall, our study reveals a previously unrecognized role of GPNMB in host Antibacterial defense and provides insights into its regulatory mechanism in SNARE complex assembly.

Keywords

GPNMB; Intracellular bacterial infection; Leprosy; SNAP29; SNARE complex; Xenophagy.

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