title: MicroRNA-155 promotes autophagy to eliminate intracellular mycobacteria by targeting Rheb.
abstract: Mycobacterium tuberculosis is a hard-to-eradicate intracellular pathogen that infects one-third of the global population. It can live within macrophages owning to its ability to arrest phagolysosome biogenesis. Autophagy has recently been identified as an effective way to control the intracellular mycobacteria by enhancing phagosome maturation. In the present study, we demonstrate a novel role of miR-155 in regulating the autophagy-mediated anti-mycobacterial response. Both in vivo and in vitro studies showed that miR-155 expression was significantly enhanced after mycobacterial infection. Forced expression of miR-155 accelerated the autophagic response in macrophages, thus promoting the maturation of mycobacterial phagosomes and decreasing the survival rate of intracellular mycobacteria, while transfection with miR-155 inhibitor increased mycobacterial survival. However, macrophage-mediated mycobacterial phagocytosis was not affected after miR-155 overexpression or inhibition. Furthermore, blocking autophagy with specific inhibitor 3-methyladenine or silencing of autophagy related gene 7 (Atg7) reduced the ability of miR-155 to promote autophagy and mycobacterial elimination. More importantly, our study demonstrated that miR-155 bound to the 3'-untranslated region of Ras homologue enriched in brain (Rheb), a negative regulator of autophagy, accelerated the process of autophagy and sequential killing of intracellular mycobacteria by suppressing Rheb expression. Our results reveal a novel role of miR-155 in regulating autophagy-mediated mycobacterial elimination by targeting Rheb, and provide potential targets for clinical treatment.
authors.affiliation: Department of Immunology, Institute of Tuberculosis Control, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China ; Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.
authors.forename: Jinli
authors.initials: J
authors.lastname: Wang
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.lastname: Minhaowu
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Lai
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Lianqiang
authors.initials: L
authors.lastname: Feng
authors.forename: Meiyu
authors.initials: M
authors.lastname: Li
authors.forename: Chunyu
authors.initials: C
authors.lastname: Huang
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhong
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050296:Microbial Viability; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D014376:Tuberculosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C502661:Atg7 protein, mouse; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; C532623:Mirn155 microRNA, mouse; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D020559:Monomeric GTP-Binding Proteins; D000071193:Autophagy-Related Protein 7