Failure and exploitation of autophagy in human pathologies—cellular integrity between inflammation, infection, and cell survival

Abstract

Autophagy is a cellular disposal system directing cargoes into lysosomes, where the substrates, ranging from proteins to pathogens, are finally subjected to proteolytic cleavage. It is well-known as a “provider” of anabolic building blocks under conditions of nutrient deprivation, but it is also evident that autophagy has implications far beyond a simple adaption to starvation in mammalian cells and organisms. This special review issue aims to summarize current knowledge regarding the involvement of autophagy in human diseases and to encourage future research in reliably detecting autophagy and manipulating autophagosome biogenesis for clinical applications. Macroautophagy represents the most extensively studied form of autophagy and involves the formation of a double membrane compartment known as the autophagosome. Within these introductory notes, we will only use the term “autophagy,” which for all topics discussed includes macroautophagy. The reviews presented in this special issue provide a sophisticated discussion on the possible involvement of other forms of autophagy in unique settings. Chloe Burman and Nicholas T. Ktistakis describe the concepts and key players of autophagosome formation, thus introducing the diversity of cellular processes that are controlled or influenced by autophagy. Furthermore, the authors demonstrate the remarkable progress made in understanding the regulation of autophagy by delineating how different cellular states like low energy levels, growth factor signaling, and starvation, can lead to increased or decreased rates of autophagosome formation. Mouse models provide crucial insights into the function of autophagy in vivo; however, the generation of genetically modified mouse strains is timeand labor-intensive, explaining why only a small portion of the mouse genome has been targeted to date. Additionally, mice lacking core autophagy genes are embryonic or neonatal lethal, thus making conditional gene targeting necessary. Further, reconstitution experiments allowing mutational analyses in vivo are not readily feasible in mice. Therefore, other model organisms are an attractive option to examine autophagy functions and pathways in vivo. One example is Drosophila, which is suitable for genetic loss-of-function induced by RNAi, as well as expression reconstitution by cDNAs immune to RNAi. This allows for the validation of specific versus off-target effects and a replacement of the wild-type protein with well-defined mutant forms [1 and references therein]. Jonathan Zirin and Norbert Perrimon give a comprehensive overview of autophagy genes and pathways that are conserved in Drosophila. Given the amount of ready-to-use tools available for Drosophila genetics, it is somewhat surprising that these resources are not more frequently and rigorously applied towards the study of autophagy functions in vivo. While some aspects of autophagy cannot be addressed, particularly the function of autophagy in adaptive immunity, Drosophila serves as a valuable model organism to study the removal of protein aggregates, autophagosome–pathogen interactions, the role of autophagy in metabolism, and other processes that control cellular logistics. To date, the autophagy pathway has been linked to a variety of human diseases. A role in cancer, especially in P. Kuballa : R. J. Xavier Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA