Wild-type rabies virus induces autophagy in human and mouse neuroblastoma cell lines

Abstract

Different rabies virus (RABV) strains have their own biological characteristics, but little is known about their respective impact on autophagy. Therefore, we evaluated whether attenuated RABV HEP-Flury and wildtype RABV GD-SH-01 strains triggered autophagy. We found that GD-SH-01 infection significantly increased the number of autophagy-like vesicles, the accumulation of enhanced green fluorescent protein (EGFP)-LC3 fluorescence puncta and the conversion of LC3-I to LC3-II, while HEP-Flury was not able to induce this phenomenon. When evaluating autophagic flux, we found that GD-SH-01 infection triggers a complete autophagic response in the human neuroblastoma cell line (SK), while autophagosome fusion with lysosomes was inhibited in a mouse neuroblastoma cell line (NA). In these cells, GD-SH-01 led to apoptosis and mitochondrial dysfunction while triggering autophagy, and apoptosis could be decreased by enhancing autophagy. To further identify the virus constituent causing autophagy, 5 chimeric recombinant viruses carrying single genes of HEP-Flury instead of those of GD-SH-01 were rescued. While the HEP-Flury virus carrying the wild-type matrix protein (M) gene of RABV triggered LC3-I to LC3-II conversion in SK and NA cells, replacement of genes of nucleoprotein (N), phosphoprotein (P) and glycoprotein (G) produced only minor autophagy. But no one single structural protein of GD-SH-01 induced autophagy. Moreover, the AMPK signaling pathway was activated by GD-SH-01 in SK. Therefore, our data provide strong evidence that autophagy is induced by GD-SH-01 and can decrease apoptosis in vitro. Furthermore, the M gene of GD-SH-01 may cooperatively induce autophagy.

BECN1-dependent CASP2 incomplete autophagy induction by binding to rabies virus phosphoprotein

“…Interestingly, BECN1 was confirmed to have an interaction with the RABV P protein. Therefore our data demonstrates for the first time a connection between BECN1 and the CASP2-mediated autophagy pathway and that RABV induces incomplete autophagy by activating the pathways BECN1-CASP2-AMPK-AKT-MTOR and BECN1-CASP2-AMPK-MAPK by BECN1 binding to viral protein P. Moreover, recent data also show an incomplete autophagic response stimulated by the viral protein M of the wild-type virulent RABV strain GD-SH-01in NA cells, 44 implying that the different components of RABV participate probably in the induction of incomplete autophagy during infection.…”

Zebrafish C-reactive protein isoforms inhibit SVCV replication by blocking autophagy through interactions with cell membrane cholesterol

“…Many viruses, including those of fish, activate/need autophagy to replicate 58,59,66,[78][79][80] . In this regard, there are some previous studies that have analysed the influence of autophagy on SVCV infection 54,57,58 ; however, the conclusions of these studies are contradictory with respect to the activation of autophagy as either a negative regulatory mechanism 54,57 or, as determined more recently, a mechanism required by the virus for replication 58 .…”

“…Although the results described above suggest that CRPs might induce autophagy, this is a debated issue for rhabdoviruses 54,[56][57][58][59] . In this context, Fig.…”

Respiratory Syncytial Virus Replication Is Promoted by Autophagy-Mediated Inhibition of Apoptosis

“…For example, hepatitis C virus (HCV), Sindbis virus, and bluetongue virus (BTV) can enhance autophagy flux (8,37,38), while hepatitis B virus (HBV), HIV, respiratory syndrome virus, and herpes simplex virus 1 (HSV-1) inhibit autophagy flux by either inhibiting autophagosome formation or blocking the fusion of autophagosome with lysosome (39)(40)(41)(42). Recently, a report even showed that different autophagy flux responses originated from different cells infected with the same strain of rabies virus (43). All these results indicate that autophagy responses are both virus and cell type specific.…”