Abstract
Mitophagy has recently been implicated in bacterial infection but the underlying mechanism remains largely unknown. Here, we uncover a role of microRNA-302/367 cluster in regulating mitophagy and its associated host response against bacterial infection. We demonstrate that miR-302/367 cluster expression was significantly increased after Pseudomonas aeruginosa infection. Enhanced expression of miR-302/367 cluster accelerated the mitophagic response in macrophages, thus increasing clearance of invading P. aeruginosa by regulating production of reactive oxygen species (ROS), while application of miR-302/367 cluster inhibitors decreased bacterial clearance. Blocking mitophagy with siRNA against mitophagy receptor prohibitin 2 (PHB2) reduced the effect of miR-302/367 cluster on induction of mitophagy and its-associated P. aeruginosa elimination. In addition, we found that miR-302/367 cluster also increased bacterial clearance in mouse model. Mechanistically, we illustrate that miR-302/367 cluster binds to the 3′-untranslated region of nuclear factor kappa B (NF-κB), a negative regulator of mitophagy, accelerated the process of mitophagy by inhibiting NF-κB. Furthermore, inhibition of NF-κB in macrophages attenuated the ROS or cytokines production and may reduce cell injury by P. aeruginosa infection to maintain cellular homeostasis. Collectively, our findings elucidate that miR-302/367 cluster functions as potent regulators in mitophagy-mediated P. aeruginosa elimination and pinpoint an unexpected functional link between miRNAs and mitophagy.
Highlights
To date, lung disease is becoming the most dangerous disease beyond the HIV/AIDS, cancer and heart disease [1]
Members of the cluster exhibited a similar trend towards upregulation in MLE-12 cells (Figures S1A, B). These findings suggest that both miR-302a and miR-302b may be involved in the process of host defense during P. aeruginosa infection and are chosen as main targets for studies
Mitophagy has been demonstrated to play an essential role in the host immune response against P. aeruginosa infection [19]
Summary
Lung disease is becoming the most dangerous disease beyond the HIV/AIDS, cancer and heart disease [1]. The selective autophagy to eliminate damaged mitochondria, is a highly conserved cellular self-digestion and catabolism process critical for maintaining cellular homeostasis [4]. Numerous autophagy-related genes (Atgs) and mitochondrial proteins are critical for activation of mitophagy and phagolysosomal maturation during microbial invasion [5, 8, 9]. Host mitochondria play key roles in resistance against bacterial infection, such as the regulation of bactericidal reactive oxygen species (ROS) [10] and inflammasome activation [11]. Besides Atgs, nuclear factor kappa B (NF-kB), a ubiquitously expressed family of Relrelated transcription factors, is involved in the regulation of autophagy [12, 13]. Whether NF-kB is involved in regulation of mitophagy remains unknown
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