Tumor Necrosis Factor α(TNFα) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of TNFα in tumor biology is complex and not completely unde...Tumor Necrosis Factor α(TNFα) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of TNFα in tumor biology is complex and not completely understood. In a human melanoma cell line, M2, and a lung carcinoma cell line, A549, TNFα up-regulates prion protein(PrP) level, and promotes tumor cell migration in a PrP dependent manner. Silencing PRNP abrogates TNFα induced tumor cell migration;this phenotype is reversed when PRNP is re-introduced. Treatment with TNFα activates nuclear factor kappa B(NF-κB)signaling, which then mitigates autophagy by reducing the expression of Forkhead Box P3(FOXP3). Down regulation of FOXP3 reduces the transcription of synaptosome associated protein 29(SNAP29), which is essential in the fusion of autophagosome and lysosome creating autolysosome. FOXP3 being a bona fide transcription factor for SNAP29 is confirmed in a promoter binding assay. Accordingly, silencing SNAP29 in these cell lines also up-regulates PrP, and promotes tumor cell migration without TNFα treatment. But, when SNAP29 or FOXP3 is silenced in these cells, they are no longer respond to TNFα. Thus, a reduction in autophagy is the underlying mechanism by which expression of PrP is up-regulated,and tumor cell migration is enhanced upon TNFα treatment. Disrupting the TNFα-NF-κB-FOXP3-SNAP29 signaling axis may provide a therapeutic approach to mitigate tumor cell migration.展开更多
细胞自噬是将细胞内受损、变性、衰老的蛋白质或细胞器清除的过程,是细胞本身的代谢需要,也是某些细胞器的更新。自噬过程涉及膜融合。可溶性N-乙基马来酰亚胺敏感的融合蛋白附着蛋白受体(soluble N-ethylmaleimide-sensitive factor at...细胞自噬是将细胞内受损、变性、衰老的蛋白质或细胞器清除的过程,是细胞本身的代谢需要,也是某些细胞器的更新。自噬过程涉及膜融合。可溶性N-乙基马来酰亚胺敏感的融合蛋白附着蛋白受体(soluble N-ethylmaleimide-sensitive factor attachment protein receptor,SNARE)之间相互作用形成SNARE复合体参与膜融合。突触样相关蛋白25(synaptosomal-associated protein of 25 kDa,SNAP25)亚家族成员包括SNAP25、SNAP23、SNAP47和SNAP29,可与其他SNARE相互作用形成SNARE复合体从而参与自噬。本文着重对SNAP25亚家族中各成员如何参与自噬,以及在自噬中所起的作用进行综述,进而为SNAP25亚家族作为疾病治疗的新靶点提供策略。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
基金supported by grants from the National Science Foundation of China (31670170 & 81560442)from MOST (2018YFA0507201)from the Natural Science Foundation of Guangdong Province (2017ZC0236)。
文摘Tumor Necrosis Factor α(TNFα) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of TNFα in tumor biology is complex and not completely understood. In a human melanoma cell line, M2, and a lung carcinoma cell line, A549, TNFα up-regulates prion protein(PrP) level, and promotes tumor cell migration in a PrP dependent manner. Silencing PRNP abrogates TNFα induced tumor cell migration;this phenotype is reversed when PRNP is re-introduced. Treatment with TNFα activates nuclear factor kappa B(NF-κB)signaling, which then mitigates autophagy by reducing the expression of Forkhead Box P3(FOXP3). Down regulation of FOXP3 reduces the transcription of synaptosome associated protein 29(SNAP29), which is essential in the fusion of autophagosome and lysosome creating autolysosome. FOXP3 being a bona fide transcription factor for SNAP29 is confirmed in a promoter binding assay. Accordingly, silencing SNAP29 in these cell lines also up-regulates PrP, and promotes tumor cell migration without TNFα treatment. But, when SNAP29 or FOXP3 is silenced in these cells, they are no longer respond to TNFα. Thus, a reduction in autophagy is the underlying mechanism by which expression of PrP is up-regulated,and tumor cell migration is enhanced upon TNFα treatment. Disrupting the TNFα-NF-κB-FOXP3-SNAP29 signaling axis may provide a therapeutic approach to mitigate tumor cell migration.
文摘细胞自噬是将细胞内受损、变性、衰老的蛋白质或细胞器清除的过程,是细胞本身的代谢需要,也是某些细胞器的更新。自噬过程涉及膜融合。可溶性N-乙基马来酰亚胺敏感的融合蛋白附着蛋白受体(soluble N-ethylmaleimide-sensitive factor attachment protein receptor,SNARE)之间相互作用形成SNARE复合体参与膜融合。突触样相关蛋白25(synaptosomal-associated protein of 25 kDa,SNAP25)亚家族成员包括SNAP25、SNAP23、SNAP47和SNAP29,可与其他SNARE相互作用形成SNARE复合体从而参与自噬。本文着重对SNAP25亚家族中各成员如何参与自噬,以及在自噬中所起的作用进行综述,进而为SNAP25亚家族作为疾病治疗的新靶点提供策略。
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.
