Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis

Li, Xuefeng; He, Sisi; Zhou, Xikun; Yan, Yonghong; Tan, Shirui; Zhang, Shuang; Li, Rongpeng; Yu, Min; Jundt, Michael C.; Hidebrand, Alec; Wang, Yongsheng; Li, Guoping; Huang, Canhua; Wu, Min

doi:10.1371/journal.ppat.1005363

Cited by 51 publications

(48 citation statements)

References 54 publications

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“…TFEB has been reported to increase the number of lysosomes and to promote bacterial clearance (14,24). In light of our data demonstrating that MPB induced biogenesis of lysosomes ( Fig.…”

Section: Mpb Triggers Tfeb Nuclear Translocation In Macrophagessupporting

confidence: 66%

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MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF‐β–activated kinase 1‐dependent activation of the transcription factor EB

et al. 2018

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Lysosome has a crucial role in clearance of endocytosed pathogens from the cell. Small molecules that can boost lysosome function and bactericidal ability to cope with subsequent infection are urgently needed. Here, we report that MPB, a novel berberine derivative, induced lysosome-based degradation and clearance of methicillin-resistant Staphylococcus aureus and enteroinvasive Escherichia coli in macrophages. MPB caused nuclear translocation of transcription factor EB (TFEB), which boosted expression of lysosome genes. TFEB silencing repressed the MPB-mediated enhancements in degradation and bacterial eradication. MPB switched on TFEB nuclear translocation by coupling 2 parallel signaling pathways. MPB-triggered JNK activation led to 14-3-3δ being released from TFEB, which, in turn, caused TFEB nuclear translocation. In addition, MPB induced AMPK activation and subsequent inhibition of mechanistic target of rapamycin activity, which also contributed to TFEB nuclear translocation. Importantly, genetical or pharmaceutical inhibition of TGF-β-activated kinase 1 (TAK1) reduced MPB action remarkably. MPB acted through TAK1 at lysine 158 to activate JNK and AMPK and, thus, induced TFEB-dependent bactericidal activity in macrophages. Therefore, our study reveals a novel mechanism by which MPB controls JNK and AMPK phosphorylation cascades to activate lysosomal function and bactericidal activity via TAK1 K158-dependent manner, which may offer insight into novel therapeutic strategies to control bacterial infection.-Liu, X., Zhang, N., Liu, Y., Liu, L., Zeng, Q., Yin, M., Wang, Y., Song, D., Deng, H. MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF-β-activated kinase 1-dependent activating the transcription factor EB.

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“…TFEB has been reported to increase the number of lysosomes and to promote bacterial clearance (14,24). In light of our data demonstrating that MPB induced biogenesis of lysosomes ( Fig.…”

Section: Mpb Triggers Tfeb Nuclear Translocation In Macrophagessupporting

confidence: 66%

“…Cells were observed by fluorescence microscopy. Alternatively, cells were lysed with PBS containing 0.1% Triton X-100, and bacterial clearance by macrophages was determined by the counting colony-forming unit (CFU) assay (24).…”

Section: Escherichia Coli Infectionmentioning

confidence: 99%

MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF‐β–activated kinase 1‐dependent activation of the transcription factor EB

et al. 2018

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“…Since recent studies indicate that autophagy is involved in lung injury (37), we set out to evaluate whether autophagy is altered in ogg-1 KO mice after hyperoxic exposure. We observed a reduction in both Atg7 and LC3-II (conversion of LC3-I to LC3-II) after exposing ogg-1 KO mice to hyperoxia (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia

Yan

Lin

Zhang

et al. 2017

The Journal of Immunology

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Oxygen is supplied as supportive treatment for patients suffering from acute respiratory distress syndrome. Unfortunately, high oxygen concentration increases reactive oxygen species (ROS) generation, which causes DNA damage and ultimately cell death in the lung. Although 8-oxoguanine-DNA glycosylase (OGG-1) is involved in repairing hyperoxia-mediated DNA damage, the underlying molecular mechanism remains elusive. Here, we report that ogg-1 deficient mice exhibited a significant increase of pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) in the lung after being exposed to 95% oxygen. In addition, we found that ogg-1 deficiency downregulated (macro)autophagy when exposed to hyperoxia both in vitro and in vivo, which was evident by decreased conversion of LC3-I to LC3-II, reduced LC3 punctate staining, and lower Atg7 expression compared to controls. Using chromatin immunoprecipitation assay, we found that OGG-1 associated with the promoter of Atg7, suggesting a role for OGG1 in regulation of Atg7 activity. Knocking down OGG-1 decreased the luciferase reporter activity of Atg7. Further, inflammatory cytokine levels in MLE-12 cells were downregulated following autophagy induction by starvation and rapamycin treatment and upregulated when autophagy was blocked using 3-methyladenine and chloroquine. atg7 KO mice and Atg7 siRNA-treated cells exhibited elevated levels of phospho-NF-κB and intensified inflammatory cytokines, suggesting that Atg7 impacts inflammatory responses to hyperoxia. These findings demonstrate that OGG-1 negatively regulates inflammatory cytokine release by coordinating molecular interaction with autophagic pathway in the hyperoxia-induced lung injury.

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“…MH-S cells were previously transfected with Rab5-RFP for 24 h [48], and then challenged with EGFP-expressing PA14 and mutants (green) at an MOI of 20:1 for 1 h. Cells were observed under an LSM 510 Meta Confocal Microscope (Carl Zeiss Micro Imaging, Thornwood, NY).…”

Section: Phagocytosis Assaymentioning

confidence: 99%

Type I CRISPR-Cas targets endogenous genes and regulates virulence to evade mammalian host immunity

et al. 2016

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Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis

Cited by 51 publications

References 54 publications

MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF‐β–activated kinase 1‐dependent activation of the transcription factor EB

MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF‐β–activated kinase 1‐dependent activation of the transcription factor EB

DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia

Type I CRISPR-Cas targets endogenous genes and regulates virulence to evade mammalian host immunity

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