GPNMB(glycoprotein non-metastatic melanoma protein B)是一种跨膜糖蛋白,广泛表达于多种细胞类型中,具有调节免疫反应、促进细胞增殖和迁移等多种生物学功能。GPNMB在维持骨代谢平衡和调控骨重塑过程中同样发挥关键作用。本文深入探...GPNMB(glycoprotein non-metastatic melanoma protein B)是一种跨膜糖蛋白,广泛表达于多种细胞类型中,具有调节免疫反应、促进细胞增殖和迁移等多种生物学功能。GPNMB在维持骨代谢平衡和调控骨重塑过程中同样发挥关键作用。本文深入探讨了GPNMB在骨生理和病理过程中的最新研究进展,包括GPNMB在维持骨量和骨质结构完整性中发挥的双重调节作用以及影响骨代谢的多条经典和新兴信号通路。另外,它在骨质疏松症、骨关节炎、骨肿瘤等骨病理过程中异常表达,参与疾病发生发展。GPNMB作为一种新型骨代谢关键调节因子的发现,为揭示骨量维持的分子基础提供了新线索,并在骨质疏松症等骨病的病因研究和靶向治疗方面具有重要的理论价值和潜在的临床转化应用前景。展开更多
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 understoo...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,Gpnmb^(fl/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.展开更多
文摘GPNMB(glycoprotein non-metastatic melanoma protein B)是一种跨膜糖蛋白,广泛表达于多种细胞类型中,具有调节免疫反应、促进细胞增殖和迁移等多种生物学功能。GPNMB在维持骨代谢平衡和调控骨重塑过程中同样发挥关键作用。本文深入探讨了GPNMB在骨生理和病理过程中的最新研究进展,包括GPNMB在维持骨量和骨质结构完整性中发挥的双重调节作用以及影响骨代谢的多条经典和新兴信号通路。另外,它在骨质疏松症、骨关节炎、骨肿瘤等骨病理过程中异常表达,参与疾病发生发展。GPNMB作为一种新型骨代谢关键调节因子的发现,为揭示骨量维持的分子基础提供了新线索,并在骨质疏松症等骨病的病因研究和靶向治疗方面具有重要的理论价值和潜在的临床转化应用前景。
基金supported by grants from the National Natural Science Foundation of China(82230107,82273545,and 82304038)the Natural Science Foundation of Shandong Province(ZR2023QH435,ZR2022MH258,and ZR2023MH046)+1 种基金the Shandong Province Taishan Scholar Project(tspd20230608)the Joint Innovation Team for Clinical&Basic Research(202410).
文摘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,Gpnmb^(fl/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.
