The lysosomal degradation pathway of autophagy plays a fundamental role in cellular, tissue, and organismal homeostasis and is mediated by evolutionarily conserved autophagy-related (ATG) genes. ...Definitive etiological links exist between mutations in genes that control autophagy and human disease, especially neurodegenerative, inflammatory disorders and cancer. Autophagy selectively targets dysfunctional organelles, intracellular microbes, and pathogenic proteins, and deficiencies in these processes may lead to disease. Moreover, ATG genes have diverse physiologically important roles in other membrane-trafficking and signaling pathways. This Review discusses the biological functions of autophagy genes from the perspective of understanding—and potentially reversing—the pathophysiology of human disease and aging.
Autophagy is a lysosomal degradation pathway that plays a fundamental role in cellular, tissue, and organismal homeostasis. Understanding the biological functions of autophagy genes gives insights into the pathophysiology of human disease and aging.
Macroautophagy (autophagy) is a conserved lysosomal degradation process essential for cellular homeostasis and adaption to stress. Accumulating evidence indicates that autophagy declines with age and ...that impaired autophagy predisposes individuals to age-related diseases, whereas interventions that stimulate autophagy often promote longevity. In this Review, we examine how the autophagy pathway restricts cellular damage and degeneration, and the impact of these functions towards tissue health and organismal lifespan.
Autophagy adjusts cellular biomass and function in response to diverse stimuli, including infection. Autophagy plays specific roles in shaping immune system development, fueling host innate and ...adaptive immune responses, and directly controlling intracellular microbes as a cell-autonomous innate defense. As an evolutionary counterpoint, intracellular pathogens have evolved to block autophagic microbicidal defense and subvert host autophagic responses for their survival or growth. The ability of eukaryotic pathogens to deploy their own autophagic machinery may also contribute to microbial pathogenesis. Thus, a complex interplay between autophagy and microbial adaptations against autophagy governs the net outcome of host-microbe encounters.
Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, ...including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens. Both specific, stimulus-dependent and more general, stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multifunctional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response.
Cells digest portions of their interiors in a process known as autophagy to recycle nutrients, remodel and dispose of unwanted cytoplasmic constituents. This ancient pathway, conserved from yeast to ...humans, is now emerging as a central player in the immunological control of bacterial, parasitic and viral infections. The process of autophagy may degrade intracellular pathogens, deliver endogenous antigens to MHC-class-II-loading compartments, direct viral nucleic acids to Toll-like receptors and regulate T-cell homeostasis. This Review describes the mechanisms of autophagy and highlights recent advances relevant to the role of autophagy in innate and adaptive immunity.
Autophagy is important for the degradation of bulk cytoplasm, long-lived proteins, and entire organelles. In lower eukaryotes, autophagy functions as a cell death mechanism or as a stress response ...during development. However, autophagy's significance in vertebrate development, and the role (if any) of vertebrate-specific factors in its regulation, remains unexplained. Through careful analysis of the current autophagy gene mutant mouse models, we propose that in mammals, autophagy may be involved in specific cytosolic rearrangements needed for proliferation, death, and differentiation during embryogenesis and postnatal development. Thus, autophagy is a process of cytosolic “renovation,” crucial in cell fate decisions.
Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned ...autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation.
Autophagy is an ancient pathway in which parts of eukaryotic cells are self-digested within the lysosome or vacuole. This process has been studied for the past seven decades; however, we are only ...beginning to gain a molecular understanding of the key steps required for autophagy. Originally characterized as a hormonal and starvation response, we now know that autophagy has a much broader role in biology, including organellar remodeling, protein and organelle quality control, prevention of genotoxic stress, tumor suppression, pathogen elimination, regulation of immunity and inflammation, maternal DNA inheritance, metabolism, and cellular survival. Although autophagy is usually a degradative pathway, it also participates in biosynthetic and secretory processes. Given that autophagy has a fundamental role in many essential cellular functions, it is not surprising that autophagic dysfunction is associated with a wide range of human diseases. Genetic studies in various fungi, particularly Saccharomyces cerevisiae, provided the key initial breakthrough that led to an explosion of research on the basic mechanisms and the physiological connections of autophagy to health and disease. The Nobel Committee has recognized this breakthrough by the awarding of the 2016 Nobel Prize in Physiology or Medicine for research in autophagy.
Highlights • Beclin orthologs are crucial regulators of autophagy and related membrane-trafficking pathways. • Multiple signaling pathways converge on Beclin 1 to regulate cellular stress responses, ...membrane trafficking, and physiology.
Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant ...conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.
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