miR-146a Inhibits dengue-virus-induced autophagy by targeting TRAF6

Abstract

During dengue virus (DENV) infection, the virus manipulates different cellular pathways to assure productive replication, including autophagy. However, it remains unclear how this autophagic process is regulated. Here, we have demonstrated a novel role for the microRNA miR-146a in negatively regulating the cellular autophagic pathway in DENV-infected A549 cells and THP-1 cells. Overexpression of miR-146a significantly blocked DENV2-induced autophagy, and LNA-mediated inhibition of miR-146a counteracted these effects. Moreover, co-overexpression of TRAF6, a target of miR-146a, significantly reversed the inhibitory effect of miR-146a on autophagy. Notably, treatment with recombinant IFN-β fully restored the autophagic activity in TRAF6-silenced cells. Furthermore, our data showed that, in DENV2-infected A549 cells, autophagy promoted a pro-inflammatory response to significantly increase TNF-α and IL-6 production. Taken together, our results define a novel role for miR-146a as a negative regulator of DENV-induced autophagy and identify TRAF6 as a key target of this microRNA in modulating the DENV-autophagy interaction.

Dengue NS5 modulates expression of miR‐590 to regulate ubiquitin‐specific peptidase 42 in human microglia

“…DENV infection targets the expression level of TRAF6 via inducing the expression of miR‐146a and diminishes IFN‐β production which facilitate viral replication . TRAF6 is also recognized as a key molecule in modulating the DENV‐autophagy interaction . In our study too, DENV infection decreases the TRAF6 expression level in human microglial cells (Figure E).…”

“…As expected, anti‐miR‐590 transfection was able to upregulate the TRAF6 expression level in microglial cells (Figure C,D). We have also checked whether DENV infection can reduce the TRAF6 expression level in microglial cells since it was earlier shown to be downregulated in other cell lines (primary human monocytes and THP‐1 cells) upon DENV infection . The TRAF6 expression level was downregulated upon 1 MOI of DENV infection in microglial cells (Figure E).…”

“…To judge overall impact of changing expression level of cellular miR‐590 on DENV pathogenesis, we checked the expression levels of TRAF6 protein upon miR‐590 mimic and anti‐miR‐590 transfection. TRAF6 is a well‐known inducer of type I interferon pathway and have been found dampened upon DENV infection in human monocytes/THP1 cell line to facilitate DENV replication . DENV infection targets the expression level of TRAF6 via inducing the expression of miR‐146a and diminishes IFN‐β production which facilitate viral replication .…”

“…Several studies related to microRNA profiling upon dengue infection have been published, which indicate its association with DENV pathogenesis. The role of miR‐146a, Let‐7e, miR‐3614‐5p, miR‐484, miR‐744, and several others are reported to influence DENV replication in different blood cell types . However, none of study so far has attempted to look into the impact of DENV on microglial microRNA profile.…”

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…Tumor necrosis factor receptor‐associated factor 6 (TRAF6) promotes autophagy by supporting ULK1 ubiquitination. miR 146a inhibits DENV‐induced autophagy by targeting TRAF6 . Hepatocellular carcinoma is one of the deadliest types of cancer and is one of the highest overall mortality compared to others.…”