Restriction of intracellular Salmonella replication by restoring TFEB-mediated xenophagy

被引:42
作者
Ammanathan, Veena [1 ]
Mishra, Piyush [1 ,2 ]
Chavalmane, Aravinda K. [1 ,3 ]
Muthusamy, Sasikumar [4 ]
Jadhav, Vidya [1 ,5 ]
Siddamadappa, Chandrashekaran [4 ]
Manjithaya, Ravi [1 ]
机构
[1] Jawaharlal Nehru Ctr Adv Sci Res, Mol Biol & Genet Unit, Autophagy Lab, Bangalore 560064, Karnataka, India
[2] Thomas Jefferson Univ, Dept Pathol, Mitocare Ctr, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA
[3] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore
[4] Vipragen Biosci Private Ltd, Mysuru, India
[5] Univ Montreal, Dept Neurosci, Quebec City, PQ, Canada
基金
英国惠康基金;
关键词
Acacetin; autolysosomes; lysosomes; MTOR-independent; Salmonella typhimurium; Salmonella-containing vacuoles; TFEB; xenophagy; HOST-DEFENSE; MYCOBACTERIUM-TUBERCULOSIS; LYSOSOMAL BIOGENESIS; AUTOPHAGY; TRANSCRIPTION; INFECTION; BACTERIA; CELLS;
D O I
10.1080/15548627.2019.1689770
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Macroautophagy/autophagy functions as a part of the innate immune system in clearing intracellular pathogens. Although this process is well known, the mechanisms that control antibacterial autophagy are not clear. In this study we show that during intracellular Salmonella typhimurium infection, the activity of TFEB (transcription factor EB), a master regulator of autophagy and lysosome biogenesis, is suppressed by maintaining it in a phosphorylated state on the lysosomes. Furthermore, we have identified a novel, antibacterial small molecule autophagy (xenophagy) modulator, acacetin. The xenophagy effect exerted by acacetin occurs in an MTOR (mechanistic target of rapamycin kinase)-independent, TFEB-dependent manner. Acacetin treatment results in persistently maintaining active TFEB in the nucleus and also in TFEB mediated induction of functional lysosomes that target Salmonella-containing vacuoles (SCVs). The enhanced proteolytic activity due to deployment of lysosomes results in clamping down Salmonella replication in SCVs. Acacetin is effective as a xenophagy compound in an in vivo mouse model of infection and reduces intracellular Salmonella burden.
引用
收藏
页码:1584 / 1597
页数:14
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