Editorial: Autophagy: From Big Data to Physiological Significance

NEZIS, IOANNIS P.; SARKAR, SOVAN; VACCARO, MARIA I.

Frontiers in Cell and Developmental Biology

Frontiers Media S.A.

Año: 2020 vol. 7

Autophagy: From Big Data to Physiological SignificanceAutophagy is a fundamental catabolic process where cytoplasmic components are sequesteredinto double-membrane vesicles called autophagosomes, which then fuse with lysosomes and theircontent is degraded. Our knowledge about autophagy sharply increased during the last decade. Thissignificant progress helped us to understand better the molecular mechanisms of autophagy and toelucidate its role in health and disease. This special issue contains a collection of three originalresearch papers and 12 review articles covering a broad range of topics highlighting how big dataand screening approaches can help toward uncovering the molecular mechanisms of autophagy.Recent years have witnessed the development of large-scale multi-omics studies on autophagyvia genomics, transcriptomics, proteomics, lipidomics, and metabolomics. Jacomin et al.comprehensively describe the omics studies undertaken in the field of autophagy, and theintegration of these omics datasets for better understanding of autophagy regulation and theinvolvement of autophagy in other biological processes. In addition, future approaches involvingsingle-cell analysis, patient-derived samples, and high-content analysis have been suggested. Theauthors also outlined the web-based resources for studying autophagy, such as for the prediction ofAtg8-family interacting proteins, and autophagy network and databases. Overall, the emerging bigdata and in silico tools not only elucidate the global landscape of autophagy but also provide criticalresources for further research in this field.There is a growing interest toward the biomedical exploitation of autophagy modulators forthe treatment of myriad human diseases. Two articles comprehensively review the screeningmethods for the drug discovery of chemical autophagy modulators. The first article by Panda et al.summarizes the in vitro chemical screening approaches for identifying autophagy modulators inmammalian cells. These methods that are commonly being used, involve reporters based on theautophagic marker LC3 or specific autophagy substrates like p62 and certain aggregation-proneproteins. The chemical screenings pertaining to the discovery of the pharmacological modulatorsof autophagy have been described. Of biomedical relevance, the therapeutic benefits of autophagymodulators have been highlighted in animal and iPSC models of selected human diseases, suchas in neurodegenerative disorders, cancer, infectious diseases, liver diseases, and myopathies, aswell as in lifespan extension. The second article by Mishra et al. primarily focuses on the chemicalbiology strategies utilizing high-throughput assays to monitor autophagy in yeast and mammaliancells. These assays are based on the growth of yeast cells, fluorescence readouts of LC3 reportersin mammalian cells, and luminescence measurements of autophagic cargo clearance includingorganelle turnover in both yeast and mammalian cells. Apart from describing the therapeutic applications of autophagy modulators, how these compounds actas valuable tools to elucidate the regulation of autophagy havealso been highlighted.For developing novel autophagy modulators, highthroughputscreens were undertaken in the research articleby Pengo et al. for identifying the regulators of ATG4B activity.The protease ATG4B is a key regulator of the LC3/GABARAPconjugation system essential for autophagosome formation.Inhibition of ATG4B activity has been suggested for cancertreatment. Through chemical and genetic screens utilizing acellular luciferase-based assay for measuring ATG4B activity,the compound STK683963 and the kinase AKT2 were identifiedas activators. Although this study focused on the enhancers ofATG4B activity, these regulators could impact on the kineticsof LC3/GABARAP processing and influence autophagy. Thedatasets of ATG4B modulators arising from the screens havebeen provided for further investigation.There is significant development in the understanding ofthe molecular mechanisms of autophagy regulation, such asthe initial steps of autophagosome biogenesis in mammals. Thereview article by Grasso et al. provides a detailed overviewof the early events in mammalian autophagosome formationincluding their membrane origins and cellular localization. Thefour major aspects outlined in this article encompass autophagyinduction via physiological stressors, autophagy initiation viamTOR and AMPK, initiation of autophagosome formationvia the ULK1 complex, and the molecular mechanisms ofphagophore generation prior to autophagosome formation.Although it was initially believed to be a bulk process, itis now well-established that autophagy is a selective process.Xenophagy is a type of selective autophagy and refers tothe selective autophagic degradation of invading bacteria andviruses, and is an important aspect of the hosts? innate immuneresponse to protect against infection. Three review articles inthis collection highlight the importance of xenophagy in diseases.Depending on the virus, autophagy can restrict or promote viralreplication, and play key roles in modulating inflammation andcell survival. Ahmad et al. provide an overview of autophagyvirusinterplay highlighting the protective role of autophagy inhuman infections. They summarize recent discoveries showingthe role of autophagy in immunity and inflammation uponviral infection. Finally, they discuss therapeutic implications andpotential caveats associated with using autophagy to controlviral infections in humans. Sharma et al., focus on bacterialdegradation by autophagy. They describe how several bacterialeffectors regulate host autophagy during infection and how thisaffects inflammation. They also present a detailed overview onthe role of several selective autophagy receptors and adaptorson bacterial xenophagy. Finally, they describe how ubiquitinligases and deubiquitinases regulate bacterial xenophagy. Evanset al., provide a comprehensive overview of the interplay betweenhost autophagy and eukaryotic pathogens. They focus oneukaryotic pathogens Plasmodium, Toxoplasma, Leishmania, andthe fungal pathogens Candida albicans, Aspergillus fumigatus,and Cryptococcus neoformans.