Publication Highlights: Dec 2015-Feb 2016 CFATG
Publication Highlights: Dec 2015-Feb 2016
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Publication Highlights: Articles on autophagy research published by french laboratories and selected by CFATG.

The human cytomegalovirus (CMV) is a DNA virus belonging to the Herpesvirus family, which owns an envelope derived from host cell membranes. CMV has a large coding capacity and has developed several mechanisms to escape the innate and adaptive immune responses. We previously demonstrated that CMV can both stimulate and block autophagy during its viral cycle in fibroblasts. The early activation of autophagy induced by the viral particle is followed by an inhibition specifically mediated by viral proteins expression. In the article Mouna et al (Autophagy 2016), we precisely identified the mechanism which allows this autophagic inhibition. The viral proteins TRS1 and IRS1 were independently able to block the formation of autophagosomes, but they can also, when they were simultaneously expressed, block the autophagic flux. Infection with different mutant viruses, which express only one of these two proteins or none of them, confirmed the action of IRS1 and TRS1 in the context of viral infection.
It is through their interaction with the autophagy machinery protein Beclin 1 (BECN1) that this inhibition happens, whereas their interaction with the protein kinase PKR, a sensor of viral infections, as described previously, plays no role in autophagy inhibition. More precisely, we showed that the coil-coiled domain of BECN1 interacts with the N terminal domain of IRS1 and that this BECN1-binding domain is essential for autophagy inhibition.
From 18h post infection, the autophagic flux was blocked in infected cells, thanks to TRS1 and IRS1. We discovered that viral production was increased when autophagy was stimulated by pharmacological modulators from that time on. Conversely, autophagy inhibition, by drugs or by shRNA shutdown, decreased CMV multiplication. Therefore, surprisingly, at least at late times of infection, autophagy appears as a proviral mechanism, the function of which remains to be precisely determined.
Autophagy. 2016 Feb;12(2):327-42
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Monitoring autophagic flux in vivo remains limited and the ideal methods relative to the techniques possible with cell culture may not exist. Recently, a few papers have demonstrated the feasibility of measuring autophagic flux in vivo by intraperitoneal injection of pharmacological agents (chloroquine, leupeptin, vinblastine, and colchicine). However, the metabolic consequences of the administration of these drugs remain largely unknown. In this paper, we report that 2 days of colchicine treatment at 0.8 mg/kg/day increased LC3-II protein levels as well as the number of autophagic vacuoles in the liver of fasted trout, supporting the usefulness of this drug for studying autophagic flux in vivo in our model organism. However, this effect was accompanied by a decrease of plasma glucose level, associated with a significant decrease of the concentration of some amino acids in the liver and a fall in the mRNA levels of gluconeogenesis-related genes. In addition, colchicine-treated trout exhibited a hepatosteatosis associated with a marked increase of hepatic triglyceride levels and a significant rise in the hepatic mRNA levels of two lipid droplet markers, Plin2 and Plin3. Concurrently, the transcript levels of ER stress-induced genes (Ddit3, Asns) as well as that of several autophagy- (p62, Atg4b) and lysosome- (Atp6v1a and Ctsd) related genes were significantly increased. Together, these results show that the concentration and/or the time period of treatment necessary to block autophagosome degradation in vivo profoundly affect metabolic and cellular homeostasis. While we cannot rule out the possibility that the observed effects are independent of autophagy inhibition, the results obtained match closely with the reported role of this degradative system, highlighting the importance of considering these effects when using not only colchicine, but all autophagy blockers as in vivo “autophagometers”.
Autophagy. 2016 Feb;12(2):343-56
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