Autophagy In Human Diseases Research Articles

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

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

Autophagy in cigarette smoke-induced chronic obstructive pulmonary disease

The molecular and cellular mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD) remain incompletely understood. We have investigated the potential role of macro-autophagy, a cellular homeostatic mechanism, in COPD and cigarette smoke-induced lung-cell injury. Autophagy is a dynamic process for the turnover of organelles and proteins, which regenerates metabolic precursors through the lysosomal-dependent catabolism of cellular macromolecules. It is typically associated with survival pathways, especially in nutrient deficiency states. The role of autophagy in human diseases is less clear, and has been associated with both protective and detrimental consequences, depending on the disease model. While autophagy is considered cytoprotective, this process is often found in association with cell death, and the relationships between autophagy and cell death remain ambiguous. We have found elevated autophagy in COPD lung specimens, as well as in response to cigarette smoke exposure in vitro and in vivo. In our studies, the activation of autophagic proteins was associated with epithelial cell apoptosis in response to cigarette smoke, with pathogenic implications in COPD. Further studies are needed to determine the functional significance of autophagy in COPD and other diseases of the lung.

Autophagy During Cardiac Stress: Joys and Frustrations of Autophagy

The study of autophagy has been transformed by the cloning of most genes in the pathway and the introduction of GFP-LC3 as a reporter to allow visual assessment of autophagy. The field of cardiac biology is not alone in attempting to understand the implications of autophagy. The purpose of this review is to address some of the controversies and conundrums associated with the evolving studies of autophagy in the heart. Autophagy is a cellular process involving a complex orchestration of regulatory gene products as well as machinery for assembly, selective targeting, and degradation of autophagosomes and their contents. Our understanding of the role of autophagy in human disease is rapidly evolving as investigators examine the process in different tissues and different pathophysiological contexts. In the field of heart disease, autophagy has been examined in the settings of ischemia and reperfusion, preconditioning, cardiac hypertrophy, and heart failure. This review addresses the role of autophagy in cardioprotection, the balance of catabolism and anabolism, the concept of mitochondrial quality control, and the implications of impaired autophagic flux or frustrated autophagy.

Autophagy in innate and adaptive immunity.

Autophagy (self-eating) is an evolutionary conserved simple process by which cells target their own cellular organelles and long-lived proteins for degradation. Recently, this simple ancient process has proved to be involved in many biological aspects, including host defense, cell survival and death, innate and adaptive immunity, and cancer. The implications of aberrant regulation of autophagy in human diseases are just beginning to unravel. This is a brief review of recent progress in the association of autophagy with innate and adaptive immunity relevant to lung biology and disease.

Coordinated regulation of autophagy by p38α MAPK through mAtg9 and p38IP

Autophagy, a lysosomal degradation pathway, is essential for homeostasis, development, neurological diseases, and cancer. Regulation of autophagy in human disease is not well understood. Atg9 is a transmembrane protein required for autophagy, and it has been proposed that trafficking of Atg9 may regulate autophagy. Mammalian Atg9 traffics between the TGN and endosomes in basal conditions, and newly formed autophagosomes in response to signals inducing autophagy. We identified p38IP as a new mAtg9 interactor and showed that this interaction is regulated by p38alpha MAPK. p38IP is required for starvation-induced mAtg9 trafficking and autophagosome formation. Manipulation of p38IP and p38alpha alters mAtg9 localization, suggesting p38alpha regulates, through p38IP, the starvation-induced mAtg9 trafficking to forming autophagosomes. Furthermore, we show that p38alpha is a negative regulator of both basal autophagy and starvation-induced autophagy, and suggest that this regulation may be through a direct competition with mAtg9 for binding to p38IP. Our results provide evidence for a link between the MAPK pathway and the control of autophagy through mAtg9 and p38IP.

Screen for Chemical Modulators of Autophagy Reveals Novel Therapeutic Inhibitors of mTORC1 Signaling

BackgroundMammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that relays nutrient availability signals to control numerous cellular functions including autophagy, a process of cellular self-eating activated by nutrient depletion. Addressing the therapeutic potential of modulating mTORC1 signaling and autophagy in human disease requires active chemicals with pharmacologically desirable properties.Methodology/Principal FindingsUsing an automated cell-based assay, we screened a collection of >3,500 chemicals and identified three approved drugs (perhexiline, niclosamide, amiodarone) and one pharmacological reagent (rottlerin) capable of rapidly increasing autophagosome content. Biochemical assays showed that the four compounds stimulate autophagy and inhibit mTORC1 signaling in cells maintained in nutrient-rich conditions. The compounds did not inhibit mTORC2, which also contains mTOR as a catalytic subunit, suggesting that they do not inhibit mTOR catalytic activity but rather inhibit signaling to mTORC1. mTORC1 inhibition and autophagosome accumulation induced by perhexiline, niclosamide or rottlerin were rapidly reversed upon drug withdrawal whereas amiodarone inhibited mTORC1 essentially irreversibly. TSC2, a negative regulator of mTORC1, was required for inhibition of mTORC1 signaling by rottlerin but not for mTORC1 inhibition by perhexiline, niclosamide and amiodarone. Transient exposure of immortalized mouse embryo fibroblasts to these drugs was not toxic in nutrient-rich conditions but led to rapid cell death by apoptosis in starvation conditions, by a mechanism determined in large part by the tuberous sclerosis complex protein TSC2, an upstream regulator of mTORC1. By contrast, transient exposure to the mTORC1 inhibitor rapamycin caused essentially irreversible mTORC1 inhibition, sustained inhibition of cell growth and no selective cell killing in starvation.Conclusion/SignificanceThe observation that drugs already approved for human use can reversibly inhibit mTORC1 and stimulate autophagy should greatly facilitate the preclinical and clinical testing of mTORC1 inhibition for indications such as tuberous sclerosis, diabetes, cardiovascular disease and cancer.