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An Intricate Link between MicroRNAs and Regulation of Autophagy in Cystic Fibrosis
Author(s) -
Tazi Mia,
Dakhlallah Duaa,
Caution Kyle,
Marsh Clay,
Amer Amal
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.571.27
Subject(s) - autophagy , microrna , inflammation , biology , innate immune system , microbiology and biotechnology , downregulation and upregulation , becn1 , burkholderia cenocepacia , immune system , immunology , cancer research , gene , genetics , apoptosis , virulence
Each year 1,000 individuals are diagnosed with Cystic Fibrosis (CF), a lethal, inherited disease characterized by severe infection and inflammation. Burkholderia cenocepacia (B.c), the most‐feared CF pathogen, harbors an innate antibiotic resistance to the majority of treatments and further exacerbates inflammation. Normally, invading microbes can be cleared through a highly‐regulated biological process called autophagy, however, this process is defective in CF. Furthermore, we demonstrated that B.c interrupts autophagic flux as it indirectly downregulates autophagy genes, causing increased bacterial burden and inflammation in CF macrophages. MicroRNAs (miRs) post‐transcriptionally regulate gene expression essential to numerous biological processes. The underlying mechanism of dysfunctional autophagy in CF macrophages remains unknown. As autophagy is a cellular innate immune response to pathogen clearance, we hypothesize that CF macrophages exhibit elevated miRNA expression that downregulate autophagy‐targeted genes thus contributing to autophagy dysfunction and facilitating infection and inflammation. qRT‐PCR results reveal a specific cluster of miRNAs, predicted to target autophagy genes, is elevated in CF macrophages. Macrophages lacking these miRs exhibit increased autophagy protein expression. Luciferase assays validate the autophagy targets of these miRs. Increased levels of active transcription factor, c‐myc, propose a mechanism for the elevated cluster level, as inhibiting c‐myc increases autophagy protein expression in CF macrophages. Together, these data demonstrate miRNA regulation of autophagy modulates the pathophysiology of CF.