Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues (original) (raw)
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Significance: Autophagy, a lysosome-dependent homeostatic process inherent to cells and tissues, has emerging significance in the pathogenesis of human disease. This process enables the degradation and turnover of cytoplasmic substrates via membrane-dependent sequestration in autophagic vesicles (autophagosomes) and subsequent lysosomal delivery of cargo. Recent Advances: Selective forms of autophagy can target specific substrates (e.g., organelles, protein aggregates, lipids) for processing. Autophagy is highly regulated by oxidative stress, including exposure to altered oxygen tension, by direct and indirect mechanisms, and contributes to inducible defenses against oxidative stress. Mitochondrial autophagy (mitophagy) plays a critical role in the oxidative stress response, through maintenance of mitochondrial integrity. Critical Issues: Autophagy can impact a number of vital cellular processes including inflammation and adaptive immunity, host defense, lipid metabolism and storage, mitochondrial homeostasis, and clearance of aggregated proteins, all which may be of significance in human disease. Autophagy can exert both maladaptive and adaptive roles in disease pathogenesis, which may also be influenced by autophagy impairment. This review highlights the essential roles of autophagy in human diseases, with a focus on diseases in which oxidative stress or inflammation play key roles, including human lung, liver, kidney and heart diseases, metabolic diseases, and diseases of the cardiovascular and neural systems. Future Directions: Investigations that further elucidate the complex role of autophagy in the pathogenesis of disease will facilitate targeting this pathway for therapies in specific diseases. This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Role of autophagy and its significance in cellular homeostasis
Applied Microbiology and Biotechnology, 2014
Autophagy is a catabolic pathway that regulates homeostasis in cells. It is an exceptional pathway of membrane trafficking. Autophagy is characterized by the formation of double-membrane vesicles; autophagosomes that are responsible for delivering damaged organelle and extra proteins to lysosome for recycling. A series of actions including environmental and genetic factors are responsible for induction of autophagy. In the past few decades, the research on autophagy has been immensely expanded because it is a vital process in maintaining cellular balance as well as deeply connected with pathogenesis of a number of diseases. The aim of this review is to present an overview of modern work on autophagy and highlight some essential genetic role in the induction of autophagy. There is an emerging need to identify, quantify, and manipulate the pathway of autophagy, due to its close relationship with a variety of developmental pathways and functions especially in cancer, diabetes, neurodegenerative disorders, and infectious diseases.
Gαq activation modulates autophagy by promoting mTORC1 signaling
Nature Communications
The mTORC1 node plays a major role in autophagy modulation. We report a role of the ubiquitous Gαq subunit, a known transducer of plasma membrane G protein-coupled receptors signaling, as a core modulator of mTORC1 and autophagy. Cells lacking Gαq/11 display higher basal autophagy, enhanced autophagy induction upon different types of nutrient stress along with a decreased mTORC1 activation status. They are also unable to reactivate mTORC1 and thus inactivate ongoing autophagy upon nutrient recovery. Conversely, stimulation of Gαq/11 promotes sustained mTORC1 pathway activation and reversion of autophagy promoted by serum or amino acids removal. Gαq is present in autophagic compartments and lysosomes and is part of the mTORC1 multi-molecular complex, contributing to its assembly and activation via its nutrient status-sensitive interaction with p62, which displays features of a Gαq effector. Gαq emerges as a central regulator of the autophagy machinery required to maintain cellular ho...
Autophagy: The spotlight for cellular stress responses
Life Sciences, 2017
Autophagy is an essential cellular mechanism which plays "housekeeping" role in normal physiological processes including removing of long lived, aggregated and misfolded proteins, clearing damaged organelles, growth regulation and ageing. Autophagy is also involved in a variety of biological functions like development, cellular differentiation, defense against pathogens and nutritional starvation. The integration of autophagy into these biological functions and other stress responses is determined by the transcriptional factors that undertake the regulatory mechanism. This review discusses the machinery of autophagy, the molecular web that connects autophagy to various stress responses like inflammation, hypoxia, ER stress, and various other pathologic conditions. Defects in autophagy regulation play a central role in number of diseases, including neurodegenerative diseases, cancer, pathogen infection and metabolic diseases. Similarly, inhibiting autophagy would contribute in the treatment of cancer. However, understanding the biology of autophagy regulation requires pharmacologically active compounds which modulate the autophagy process. Inducers of autophagy are currently receiving considerable attention as
Molecular Mechanisms of Autophagy in the Cardiovascular System
Circulation Research, 2015
Autophagy is a catabolic recycling pathway triggered by various intra-or extracellular stimuli that is conserved from yeast to mammals. During autophagy, diverse cytosolic constituents are enveloped by double-membrane vesicles, autophagosomes, which later fuse with lysosomes or the vacuole to degrade their cargo. Dysregulation in autophagy is associated with a diverse range of pathologies including cardiovascular disease, the leading cause of death in the world. Accordingly, there is tremendous interest in modulating autophagy for therapeutic purposes. One complexity with regard to cardiovascular homeostasis, however, is that the timing of autophagic activity appears to be critical; for example, cardiomyocyte autophagy during ischemia/reperfusion can be either beneficial or harmful. Here, we review the molecular mechanisms that govern autophagosome formation and analyze the link between autophagy and cardiovascular disease.
Student Signature: _________________________________________________________________________________ Faculty Signature: _________________________________________________________________________________ Introduction. Our laboratory investigates vascular function in response to pathophysiological (e.g., obesity/type 2 diabetes, ischemia, hypertension), physiological (e.g., physical exercise), and nutritional (e.g., polyphenolic compounds) interventions using human, animal, isolated vessel, and cell culture models. More recently the focus of our research has been centered on the process of autophagy. Autophagy ("self-eating") is a general term for the conserved intracellular process or system whereby organelles within the cytoplasm of a cell are degraded via lysosomes. Autophagy plays a central role in cellular quality control by degrading damaged or excess proteins, lipids, membranes, and organelles that accumulate in the normal life of a cell and / or in response to deviations from homeostasis. There are three different categories of autophagy-macroautophagy, microautophagy, and chaperone-mediated autophagy. When the term "autophagy" is used it indicates macroautophagy unless otherwise specified 5 . Macroautophagy is divided further into two subcategories: induced and basal autophagy 6 .
Autophagy at the interface of endothelial cell homeostasis and vascular disease
The FEBS journal, 2021
Autophagy is an essential intracellular process for cellular quality control. It enables cell homeostasis through the selective degradation of harmful protein aggregates and damaged organelles. Autophagy is essential for recycling nutrients, generating energy to maintain cell viability in most tissues and during adverse conditions such as hypoxia/ischaemia. The progressive understanding of the mechanisms modulating autophagy in the vasculature has recently led numerous studies to link intact autophagic responses with endothelial cell (EC) homeostasis and function. Preserved autophagic flux within the ECs has an essential role in maintaining their physiological characteristics, whereas defective autophagy can promote endothelial pro-inflammatory and atherogenic phenotype. However, we still lack a good knowledge of the complete molecular repertoire controlling various aspects of endothelial autophagy and how this is associated with vascular diseases. Here, we provide an overview of th...
Autophagy modulation as a potential therapeutic target for diverse diseases
Nature Reviews Drug Discovery, 2012
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 doublemembraned 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.
Proceedings of the American Thoracic Society, 2010
Autophagy, or "self eating," refers to a regulated cellular process for the lysosomal-dependent turnover of organelles and proteins. During starvation or nutrient deficiency, autophagy promotes survival through the replenishment of metabolic precursors derived from the degradation of endogenous cellular components. Autophagy represents a general homeostatic and inducible adaptive response to environmental stress, including endoplasmic reticulum stress, hypoxia, oxidative stress, and exposure to pharmaceuticals and xenobiotics. Whereas elevated autophagy can be observed in dying cells, the functional relationships between autophagy and programmed cell death pathways remain incompletely understood. Preclinical studies have identified autophagy as a process that can be activated during vascular disorders, including ischemia-reperfusion injury of the heart and other organs, cardiomyopathy, myocardial injury, and atherosclerosis. The functional significance of autophagy in huma...