Figure 2.

Indirect effects of viruses on the autophagy pathway through deregulation of cellular miRNAs

Autophagy involves the spatially and temporarily coordinated activation of multiple molecular components, including the ULK1 (UNC-51-like kinase 1), FIP200 (FAK family kinase-interacting protein of 200 kDa), and ATG13–ATG101 complex, which is functionally coupled to the negative autophagy regulator, mTOR complex 1, and initiates autophagy. The lipid kinase vacuolar protein sorting 34 (VPS34)-Beclin-1 complex is usually inactivated by anti-apoptotic proteins from the BCL-2 family, but when it is activated it drives the nucleation of the isolation membrane.¹⁵ The AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway is well known to be associated with autophagy, and AMPK can promote the initiation of autophagy. Activation of AMPK can result in the inhibition of mTOR, which is commonly activated in malignant cells.¹⁶ miR-106a is upregulated by the HPV-16 E7 oncogene and stimulates cell proliferation and suppresses autophagy by targeting LKB1 via the AMPK-mTOR pathway in HPV-16-associated cervical cancer. Autophagy contributes to HBV replication, as confirmed by observations that autophagy inhibition strongly impaired replication of HBV in liver cells. The expression level of miR-155 was upregulated in HBV-infected cells, and miR-155 reinforced HBV replication by affecting the SOCS1/Akt/mTOR-autophagy axis. HBV also promoted autophagy through the miR-192-3p-XIAP axis, which is important for HBV replication in vitro and in vivo. Beclin-1 is a key autophagy-promoting gene in the early phase of autophagosome formation. It has been shown that EV71 infection induced autophagosome formation through the reduction of cellular miR-30a, which led to the inhibition of Beclin-1.