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Mycobacterium tuberculosis-induced miR-155 subverts autophagy by targeting ATG3 in human dendritic cells.
Etna, Marilena P; Sinigaglia, Alessandro; Grassi, Angela; Giacomini, Elena; Romagnoli, Alessandra; Pardini, Manuela; Severa, Martina; Cruciani, Melania; Rizzo, Fabiana; Anastasiadou, Eleni; Di Camillo, Barbara; Barzon, Luisa; Fimia, Gian Maria; Manganelli, Riccardo; Coccia, Eliana M.
Afiliação
  • Etna MP; Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
  • Sinigaglia A; Department of Molecular Medicine, University of Padova, Padua, Italy.
  • Grassi A; Department of Information Engineering, University of Padova, Padua, Italy.
  • Giacomini E; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy.
  • Romagnoli A; Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
  • Pardini M; National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy.
  • Severa M; Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
  • Cruciani M; Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
  • Rizzo F; Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
  • Anastasiadou E; Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
  • Di Camillo B; Department of Pathology, Institute for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.
  • Barzon L; Department of Information Engineering, University of Padova, Padua, Italy.
  • Fimia GM; Department of Molecular Medicine, University of Padova, Padua, Italy.
  • Manganelli R; National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy.
  • Coccia EM; Department of Biological and Environmental Science and Technology, University of Salento, Lecce, Italy.
PLoS Pathog ; 14(1): e1006790, 2018 01.
Article em En | MEDLINE | ID: mdl-29300789
Autophagy is a primordial eukaryotic pathway, which provides the immune system with multiple mechanisms for the elimination of invading pathogens including Mycobacterium tuberculosis (Mtb). As a consequence, Mtb has evolved different strategies to hijack the autophagy process. Given the crucial role of human primary dendritic cells (DC) in host immunity control, we characterized Mtb-DC interplay by studying the contribution of cellular microRNAs (miRNAs) in the post-transcriptional regulation of autophagy related genes. From the expression profile of de-regulated miRNAs obtained in Mtb-infected human DC, we identified 7 miRNAs whose expression was previously found to be altered in specimens of TB patients. Among them, gene ontology analysis showed that miR-155, miR-155* and miR-146a target mRNAs with a significant enrichment in biological processes linked to autophagy. Interestingly, miR-155 was significantly stimulated by live and virulent Mtb and enriched in polysome-associated RNA fraction, where actively translated mRNAs reside. The putative pair interaction among the E2 conjugating enzyme involved in LC3-lipidation and autophagosome formation-ATG3-and miR-155 arose by target prediction analysis, was confirmed by both luciferase reporter assay and Atg3 immunoblotting analysis of miR-155-transfected DC, which showed also a consistent Atg3 protein and LC3 lipidated form reduction. Late in infection, when miR-155 expression peaked, both the level of Atg3 and the number of LC3 puncta per cell (autophagosomes) decreased dramatically. In accordance, miR-155 silencing rescued autophagosome number in Mtb infected DC and enhanced autolysosome fusion, thereby supporting a previously unidentified role of the miR-155 as inhibitor of ATG3 expression. Taken together, our findings suggest how Mtb can manipulate cellular miRNA expression to regulate Atg3 for its own survival, and highlight the importance to develop novel therapeutic strategies against tuberculosis that would boost autophagy.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Células Dendríticas / MicroRNAs / Enzimas de Conjugação de Ubiquitina / Proteínas Relacionadas à Autofagia / Mycobacterium tuberculosis Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: PLoS Pathog Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Células Dendríticas / MicroRNAs / Enzimas de Conjugação de Ubiquitina / Proteínas Relacionadas à Autofagia / Mycobacterium tuberculosis Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: PLoS Pathog Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Itália