Dengue virus non structural protein 1 disrupts the TGF-β/Smad signaling by utilizing E3 ligase Smurf2

Abstract

TGF-β signaling is tightly regulated to ensure cellular functions. Role of DENV on the TGF-β/Smad signaling has not been well established. Therefore, we aimed to study the association between DENV replication and TGF-β/Smad signaling. We observed impaired expression of Smad2/3/4 during DENV replication along with significant reduction in the expression of phosphorylated Smad3. Overexpression of Smad6/7 showed inhibitory effect on DENV replication. We observed DENV-NS1 not only physically interacts with Smad2/3/4 but also impaired their expression by utilizing Smurf2 E3 ligase. Co-immunoprecipitation of NS1 and Smurf2 suggests that NS1 may acts as a co-factor to escalate the lysosomal mediated degradation of Smads. Additionally we observed, NS1 is capable of blocking the nuclear translocation of Smad3 and thus further ensuring inhibition of Smad signaling. Therefore, our results confirm that DENV-NS1 interacts with Smads and reduces their expression that may favor in virus replication.