MicroRNA-155 Promotes Autophagy to Eliminate Intracellular Mycobacteria by Targeting Rheb

Wang, Jinli; Yang, Kun; Zhou, Lin; MinhaoWu,; Wu, Yongjian; Zhu, Min; Lai, Xiaomin; Chen, Tao; Feng, Lianqiang; Li, Meiyu; Huang, Chunyu; Zhong, Qian; Huang, Xi

doi:10.1371/journal.ppat.1003697

Cited by 230 publications

(208 citation statements)

References 65 publications

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“…ZO‐1 upregulation was also reported after the in vivo inhibition of miR‐155. In these studies, we proposed that ZO‐1 stabilization was mediated by miR‐155 direct target protein Ras homolog enriched in brain (Rheb) 18, 27. However, in the present study, Rheb levels were not affected by miR‐155 inhibition or overexpression (which probably means that in vivo experiments detected the combined Rheb levels in the endothelial cells, as well as microglia and astrocytes).…”

Section: Resultscontrasting

confidence: 75%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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BackgroundBrain microvascular endothelial cells form a highly selective blood brain barrier regulated by the endothelial tight junctions. Cerebral ischemia selectively targets tight junction protein complexes, which leads to significant damage to cerebral microvasculature. Short noncoding molecules called microRNAs are implicated in the regulation of various pathological states, including endothelial barrier dysfunction. In the present study, we investigated the influence of microRNA‐155 (miR‐155) on the barrier characteristics of human primary brain microvascular endothelial cells (HBMECs).Methods and ResultsOxygen‐glucose deprivation was used as an in vitro model of ischemic stroke. HBMECs were subjected to 3 hours of oxygen‐glucose deprivation, followed by transfections with miR‐155 inhibitor, mimic, or appropriate control oligonucleotides. Intact normoxia control HBMECs and 4 oxygen‐glucose deprivation–treated groups of cells transfected with appropriate nucleotide were subjected to endothelial monolayer electrical resistance and permeability assays, cell viability assay, assessment of NO and human cytokine/chemokine release, immunofluorescence microscopy, Western blot, and polymerase chain reaction analyses. Assessment of endothelial resistance and permeability demonstrated that miR‐155 inhibition improved HBMECs monolayer integrity. In addition, miR‐155 inhibition significantly increased the levels of major tight junction proteins claudin‐1 and zonula occludens protein‐1, while its overexpression reduced these levels. Immunoprecipitation and colocalization analyses detected that miR‐155 inhibition supported the association between zonula occludens protein‐1 and claudin‐1 and their stabilization at the HBMEC membrane. Luciferase reporter assay verified that claudin‐1 is directly targeted by miR‐155.ConclusionsBased on these results, we conclude that miR‐155 inhibition–induced strengthening of endothelial tight junctions after oxygen‐glucose deprivation is mediated via its direct target protein claudin‐1.

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Section: Resultscontrasting

confidence: 75%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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“…For example, hypoxia induced miR-155 promotes autophagic activity through targeting Rheb and other component in mTOR signaling. 23,24 miR-34a inhibits autophagy and enhances chemotherapy-induced apoptosis in the retinoblastoma cell through HMGB1. 25 The miR-15a/107 group of miRNA contains a series of miRNAs, including miR-15a, miR-15b, miR-16, miR-103 and miR-107 family.…”

Section: Introductionmentioning

confidence: 99%

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

Huang

Qiu

et al. 2015

Cancer Biology & Therapy

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Abbreviations: BAFA1, bafilomycin A1; CPT, Camptothecin; miRNA, microRNA; LC3, microtubule-associated protein 1 light chain 3; mTOR, mechanistic target of rapamycin; Rictor, Rptor independent companion of mTOR complex 2; MUT, mutated; UTR, untranslated region; NC, negative control.It has been reported that persistent or excessive autophagy promotes cancer cell death during chemotherapy, either by enhancing the induction of apoptosis or mediating autophagic cell death. Here, we show that miR-15a and miR-16 are potent inducers of autophagy. Rictor, a component of mTORC2 complex, is directly targeted by miR-15a/16. Overexpression of miR-15a/16 or depletion of endogenous Rictor attenuates the phosphorylation of mTORC1 and p70S6K, inhibits cell proliferation and G1/S cell cycle transition in human cervical carcinoma HeLa cells. Moreover, miR15a/16 dramatically enhances anticancer drug camptothecin (CPT)-induced autophagy and apoptotic cell death in HeLa cells. Collectively, these data demonstrate that miR-15a/16 induced autophagy contribute partly to their inhibition of cell proliferation and enhanced chemotherapeutic efficacy of CPT.

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“…The physiological importance of the host miRNA-autophagy interconnection is only beginning to be decoded during the course of bacterial infection. 36,39,40 However, it represents a new understanding of the post-transcriptional regulatory control of autophagy by miRNAs. The exact mechanistic details of host microRNAs in regulating the autophagy process during the course of Leishmania infection remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…38 In the past several years, accumulating evidence suggests post-transcriptional controls mediated by noncoding miRNAs significantly influence the process of autophagy in cancer, and most recently during infection with viruses and intracellular pathogens. 22,[39][40][41] The miRNA-based modulation of autophagy process is achieved at the level of cell cycle control, genotoxic stress and hypoxia among others. 42 BECN1 is a central molecule that lies at the crossroads of the process of autophagy and apoptosis depending on its differential interaction with key proteins that regulate the process of cell survival inside the cell.…”

Section: Discussionmentioning

confidence: 99%

“…49 The role of miRNAs in controlling intracellular pathogens such as Mycobacterium and Salmonella is well documented and several microRNAs including MIR30A and MIR155 play key roles in regulating autophagy process by targeting several key molecules regulating the process of autophagy during the course of infection in human macrophages. 36,39 As the information accumulates, there is an urgent need to look into the regulatory mechanisms controlling the host cell autophagy during pathogenic challenge. This information further carries the merit to identify potential antipathogenic therapeutics and decipher the basic information related to the infection process.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA expression profiling ofLeishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy

et al. 2016

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Leishmania is an obligate intracellular parasite that replicates inside phagolysosomes or parasitophorous vacuoles (PV) of the monocyte/macrophage lineage. It reprograms macrophages and produces a metabolic state conducive to successful infection and multiplication. MicroRNAs (miRNAs), a class of small 22 to 24 nucleotide noncoding regulatory RNAs alter the gene expression and consequently proteome output by targeting mRNAs, may play a regulatory role in modulating host cell functions. In the present study, we demonstrate the novel regulatory role of host microRNA, MIR30A-3p in modulation of host cell macroautophagy/autophagy after infection with L. donovani. Our in vitro studies showed that MIR30A-3p expression was significantly enhanced after L. donovani infection in a time-dependent manner. Transient transfection with a MIR30A-3p inhibitor followed by L. donovani infection promoted the autophagic response and decreased the intracellular parasite burden in both THP-1 cells and human monocytederived macrophages (HsMDM). BECN1/Beclin 1, the mammalian ortholog of yeast Vps30/Atg6, is a key autophagy-promoting protein that plays a key role in the regulation of cell death and survival. We report BECN1-dependent modulation of host cell autophagy in response to L. donovani infection. Pretreatment of L. donovani-infected macrophages with the MIR30A-3p mimic decreased and with antagomir increased the expression of BECN1 protein. We demonstrate that BECN1 is a potential target of MIR30A-3p and this miRNA negatively regulates BECN1 expression. Our present study reveals for the first time a novel role of MIR30A-3p in regulating autophagy-mediated L. donovani elimination by targeting BECN1. The present study has significant impact for the treatment of visceral leishmaniasis.

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MicroRNA-155 Promotes Autophagy to Eliminate Intracellular Mycobacteria by Targeting Rheb

Cited by 230 publications

References 65 publications

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

MicroRNA expression profiling ofLeishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy

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