Through activation of the CD GOPC pathway attenuated vaccina

Through activation of the CD46–GOPC pathway, attenuated/vaccinal MeVs rapidly induce a transient phase of autophagy which then diminishes with no signs of negative regulation and precedes a second autophagy phase related to viral protein synthesis [115]. In sharp contrast, virulent MeVs do not interact with CD46 and fail to induce early autophagy in infected cells. This functional pattern raises the question of a putative relationship between such an early autophagy induction and the vaccinal status of these strains. Possibly, signaling, or cellular events, associated with early autophagy could play a role in the vaccinal status, for instance, through induction of anti-viral pathways or through efficient degradation of particular viral factors that rapidly give advantage to the immune system [116]. Further investigation is needed to explore this possibility. Other important issues that relate to the interaction of viruses with the autophagy machinery during early phases of infection include the consequences of these interactions on the epigenetic and transcriptional regulation of autophagy that is involved in immediate response to autophagy stimulation [117], the potential impacts on non-coding RNAs and RNA-binding proteins able to regulate core autophagy [118], whether early virus–host cell interactions impact the functioning of components of the cytoskeleton that are important for the autophagy flux [119], whether there exist particular autophagy receptors engaged during autophagic responses associated with early virus–host cell interactions and whether the interactions described in in-vitro models of infection can be consistently recapitulated in vivo. Because viruses and their hosts are coevolving for a very long period of time, a complex relationship between viruses and the autophagy machinery has evolved. Dissecting such a relationship will permit a better understanding of the early steps of the life Vidofludimus synthesis of viruses, of the nature of autophagy as a cell-autonomous defense mechanism and of the various strategies viruses use to counteract this defense. Finally, it will be interesting to assess to which extend the autophagy process can be effectively oriented for therapeutic purposes as the regulation of autophagosome biogenesis, maturation and lysosomal degradation are better characterized and potentially druggable [120]. In the same vein, strategies aiming at the manipulation of host factors used by viruses to counteract autophagic responses should be explored especially in the case of viruses for which therapies have been complicated to develop.
Acknowledgments Our work is supported by ANR-14-CE14-0022, Fondation pour la Recherche Médicale (FRM) DEQ20170336729, Société Nationale Française de Gastro-entérologie (SNFGE) and Association François Aupetit (AFA). We apologize to colleagues whose work could not be referenced due to space limitations.
Neuronal Autophagy: New Views Autophagy is a catabolic process that degrades macromolecules and organelles by delivering them to the lysosome. Three mechanistically distinct types, microautophagy, chaperone-mediated autophagy, and macroautophagy, have been described 1, 2. Unlike the first two types, macroautophagy is a multistep process that entails the formation of a double-membrane vesicle, the autophagosome. The mechanisms of macroautophagy have been reviewed [3]. Briefly, autophagosome biogenesis starts with the assembly of a pre-autophagosomal structure (PAS), which is necessary for the nucleation (see Glossary) of a phagophore. The phagophore is a double-membrane structure that sequesters autophagic cargo as it elongates and closes to form the autophagosome. Here, we will focus on macroautophagy, which will be referred to hereafter as autophagy. Autophagy was regarded as a housekeeping process that ensured the clearance of unwanted materials and prevented their aggregation in order to safeguard cellular function. Early work investigating the role of autophagy in the brain indicated that conditional ablation in the nervous system of core autophagy genes, such as atg5 or atg7, led to the accumulation of aggregates of ubiquitinated proteins in neurons and late onset neurodegeneration 4, 5. However, recent work suggests that in addition to cellular maintenance, autophagy can also facilitate the homeostasis of specific proteins in a microenvironment or be regulated by neuronal signalling and activity, thus contributing to specialized neuronal functions. This is consistent with the realization that autophagy is not a generalized process but is capable of high selectivity in cargo sequestration. In the brain, several studies have delineated the requirement of autophagy in hypothalamic neurons for the regulation of nutrient uptake 6, 7, 8, 9. However, the role of autophagy in other neuronal functions, such as synaptic mechanisms that underlie complex cognitive functions, is only beginning to unravel. Here, we overview the regulation of autophagy in different neuronal compartments and discuss its roles in synapses.