Autophagy–mediated plasma membrane removal promotes the formation of epithelial syncytia

Epithelial wound healing in Drosophila involves the formation of multinucleate cells surrounding the wound. We show that autophagy, a cellular degradation process often deployed in stress responses, is required for the formation of a multinucleated syncytium during wound healing, and that autophagosomes that appear near the wound edge acquire plasma membrane markers. In addition, uncontrolled autophagy in the unwounded epidermis leads to the degradation of endo‐membranes and the lateral plasma membrane, while apical and basal membranes and epithelial barrier function remain intact. Proper functioning of TORC1 is needed to prevent destruction of the larval epidermis by autophagy, in a process that depends on phagophore initiation and expansion but does not require autophagosomes fusion with lysosomes. Autophagy induction can also affect other sub‐cellular membranes, as shown by its suppression of experimentally induced laminopathy‐like nuclear defects. Our findings reveal a function for TORC1‐mediated regulation of autophagy in maintaining membrane integrity and homeostasis in the epidermis and during wound healing.     

Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy

Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals.     

A picky eater: exploring the mechanisms of selective autophagy in human pathologies

Autophagy is a catabolic process conserved among all eukaryotes essential for the cellular and organismal homeostasis. One of the principal roles of this pathway is to maintain an accurate balance between synthesis, degradation and subsequent recycling of cellular components. Under certain conditions, however, cells are also able to modulate autophagy and specifically remove a number of structures that are potentially harmful. Aberrant protein aggregates, damaged organelles or pathogens can be selectively incorporated into large double-membrane vesicles called autophagosomes to be delivered into lysosomes for destruction. This ability to eliminate specific structures is exploited by the cells in several physiological processes as well as in multiple pathological situations, making autophagy a precious multitask cellular degradative pathway. In this review, we will first examine what is known about the basic mechanisms of autophagy and then discuss in a second part the nature of the cargoes that are selectively sequestered into autophagosomes, what provides the specificity and the possible implications of selective types of autophagy in human pathologies.     

Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy‐related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.     

Autophagy in innate immunity against intracellular bacteria

Many pathogenic bacteria can invade phagocytic and non-phagocytic cells and colonize them intracellularly, then become disseminated to other cells. The endocytic degradation pathway is thought to be the only prevention against such intracellular pathogens. Autophagy, a fundamental cellular homeostasis pathway that operates with the intracellular degradation/recycling system, causes the turnover of cellular components by delivering portions of the cytoplasm and organelles to lysosomes. Recently, we reported that autophagic degradation is a previously unrecognized effector of host innate immunity. Streptococcus pyogenes (Group A Streptococcus; GAS) successfully enters human epithelial cells via endocytosis. GAS immediately escapes from the endosomes to the cytoplasm and gains a replicative niche, after which GAS in the cytoplasm is trapped in autophagosome-like compartments and degraded upon fusion with lysosomes. This process indicates that autophagy plays a protective role in infectious diseases. We also found that autophagic degradation was induced against Staphylococcus aureus, while methicillin-resistant S. aureus were resistant to autophagic degradation. The present review focuses on the protective function of autophagy against bacterial invasion of cells.     

Autophagy process is associated with anti-neoplastic function

Autophagy is a highly conserved process of cellular degradation, which is present in yeast, plants, and mammals. Under normal physiological conditions, autophagy acts to maintain cellular homeostasis and regulate the turnover of organelles. In response to cellular stresses, autophagy prevents the accumulation of impaired proteins and organelles, which serves to inhibit carcinogenesis. On this basis, it is widely accepted that most tumor suppressors, such as beclin 1 associated proteins, forkhead box class O (FoxO) family proteins, multiple mammalian target of Rapamycin (mTOR) inactivators, and nuclear p53 play a role in inducing autophagy. Here, we focus on how the process of autophagy is associated with anti-neoplastic function.     

自噬对血管功能的影响及与相关疾病的关联研究进展

自噬(autophagy)是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程,在稳定细胞内环境中发挥着重要作用．研究发现,自噬影响血管功能,与血管疾病的病理生理进程密切相关．本文从自噬对血管功能的影响,与血管相关疾病(如动脉粥样硬化、腹主动脉瘤、肺动脉高压、糖尿病血管并发症等)的关系及药物对血管壁细胞自噬的调控进行综述,希望从自噬的角度来了解血管的功能和病变及一些疾病的发生发展进程,为治疗血管相关疾病提供新的思路．     

Autophagy in cardiomyopathies

Autophagy (greek auto: self; phagein: eating) is a highly conserved process within eukaryotes that degrades long-lived proteins and organelles within lysosomes. Its accurate and constant operation in basal conditions ensures cellular homeostasis by degrading damaged cellular components and thereby acting not only as a quality control but as well as an energy supplier. An increasing body of evidence indicates a major role of autophagy in the regulation of cardiac homeostasis and function. In this review, we describe the different forms of mammalian autophagy, their regulations and monitoring with a specific emphasis on the heart. Furthermore, we address the role of autophagy in several forms of cardiomyopathy and the options for therapy.     

Self-eating in skeletal development: Implications for lysosomal storage disorders

Macroautophagy (a.k.a. autophagy) is a cellular process aimed at the recycling of proteins and organelles that is achieved when autophagosomes fuse with lysosomes. Accordingly, lysosomal dysfunctions are often associated with impaired autophagy. We demonstrated that inactivation of the sulfatase modifying factor 1 gene (Sumf1), a gene mutated in Multiple Sulfatase Deficiency (MSD), causes glycosaminoglycans (GAGs) to accumulate in lysosomes, which in turn disrupts autophagy. We utilized a murine model of MSD to study how impairment of this process affects chondrocyte viability and thus skeletal development.     

Role of autophagy in breast cancer

Autophagy is an evolutionarily conserved process of cytoplasm and cellular organelle degradation in lysosomes. Autophagy is a survival pathway required for cellular viability during starvation; however, if it proceeds to completion, autophagy can lead to cell death. In neurons, constitutive autophagy limits accumulation of polyubiquitinated proteins and prevents neuronal degeneration. Therefore, autophagy has emerged as a homeostatic mechanism regulating the turnover of long-lived or damaged proteins and organelles, and buffering metabolic stress under conditions of nutrient deprivation by recycling intracellular constituents. Autophagy also plays a role in tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in many human ovarian, breast, and prostate cancers, and beclin1(+/-) mice are tumor-prone. We found that allelic loss of beclin1 renders immortalized mouse mammary epithelial cells susceptible to metabolic stress and accelerates lumen formation in mammary acini. Autophagy defects also activate the DNA damage response in vitro and in mammary tumors in vivo, promote gene amplification, and synergize with defective apoptosis to accelerate mammary tumorigenesis. Thus, loss of the prosurvival role of autophagy likely contributes to breast cancer progression by promoting genome damage and instability. Exploring the yet unknown relationship between defective autophagy and other breast cancer promoting functions may provide valuable insight into the pathogenesis of breast cancer and may have significant prognostic and therapeutic implications for breast cancer patients.     

Viruses and the autophagy machinery

Autophagy is a major intracellular pathway for degradation and recycling of long-lived proteins and cytoplasmic organelles that plays an essential role in maintenance of homeostasis in response to starvation and other cellular stresses. Autophagy is also important for a variety of other processes including restriction of intracellular pathogen replication. Our understanding of the fascinating relationship between viruses and the autophagy machinery is still in its infancy but it is clear that autophagy is a newly recognized facet of innate and adaptive immunity against viral infection. Although the autophagy pathway is emerging as a component of host defense, certain viruses have developed strategies to counteract these antiviral mechanisms, and others appear to have co-opted the autophagy machinery as proviral host factors favoring viral replication. The complex interplay between autophagy and viral infection will be discussed in this review.     

Autophagy is a regulator of TRAIL-induced apoptosis in NSCLC A549 cells

Autophagy, a catabolic process by which cytoplasmic components are degraded in lysosomes, plays an important role in the maintenance of cellular homeostasis. Dysregulation of autophagy is associated with several diseases. However, few studies have addressed the role of autophagy in the lung, and its role in lung diseases remains unclear. In the present study, we examined the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on autophagy in A549 cells and explored the underlying mechanisms. We showed that TRAIL promoted autophagosome formation, as detected by the levels of LC3-II, and its effect on promoting autophagy was dependent on the expression of the autophagy related genes (ATGs) Atg5, Atg7, and beclin-1. TRAIL-induced ATG expression was attenuated by JNK silencing or treatment with the JNK inhibitor SP600125, indicating the involvement of the JNK pathway. Crosstalk between autophagy and apoptosis was demonstrated by silencing the autophagy related genes Atg5, Atg7, and beclin-1, and the dependence of TRAIL-induced apoptosis on autophagy-related gene expression. Taken together, our results indicate that TRAIL promotes autophagy in A549 cells via a mechanism involving the modulation of ATG expression through the JNK pathway. Inhibition of autophagy enhanced TRAIL-induced cell proliferative inhibition and apoptosis in A549 cells.     

Mechanisms of autophagy and pexophagy in yeasts

Autophagy is a process of recycling of the intracellular constituents using vacuoles (lysosomes). General autophagy occurs due to involvement of highly conservative components found in all eukaryotes, from yeasts to higher plants and humans. Autophagy also could be a selective process and be involved in regulation of the cellular number of organelles, including that of peroxisomes. The process of specific autophagic peroxisome degradation is known as pexophagy. Yeasts appear to be convenient model for studying molecular mechanisms of pexophagy, and most known ATG genes (from the term AuTophaGy) were identified in yeast studies. This review examines characteristics of general autophagy, other types of autophagy as well as pexophagy, in particular, functions of Atg proteins in general autophagy and in macro- and micropexophagy. Special attention is given to mechanisms of phagophore assembly, the role of phosphatidylinositol-3-phosphate in pexophagy, the role of peroxines (proteins involved in peroxisome biogenesis) in pexophagy, as well as properties of Atg proteins specifically involved in micropexophagy.     

细胞自噬与肿瘤

自噬是广泛存在于真核细胞内的一种细胞分解自身构成成分的生命现象.细胞内的双层膜结构与溶酶体结合后其内包裹的受损、变形或衰老细胞器蛋白质等被水解酶类降解.细胞自噬具有多种生理功能,生命体借此维持蛋白质代谢平衡及细胞环境稳定,这一过程在细胞清除废物、结构重建、生长发育调节中发挥重要作用. 细胞自噬也与肿瘤的存活和死亡等过程密切相关. 近年来对细胞自噬的研究有了较大的深入,本文主要对自噬体的形态和发生过程及其分子机制、信号调节通路、自噬研究的检测方法,以及自噬与细胞凋亡和肿瘤发生的关系等方面进行概述,以期较全面地了解细胞自噬作用和最新研究动态.     

Genes for plant Autophagy: Functions and interactions

Autophagy, or self-consuming of cytoplasmic constituents in a lytic compartment, plays a crucial role in nutrient recycling, development, cell homeostasis, and defense against pathogens and toxic products. Autophagy in plant cells uses a conserved machinery of core Autophagy-related (Atg) proteins. Recently, research on plant autophagy has been expanding and other components interacting with the core Atg proteins are being revealed. In addition, growing evidence suggests that autophagy communicates with other cellular pathways such as the ubiquitin-proteasome system, protein secretory pathway, and endocytic pathway. An increase in our understanding of plant autophagy will undoubtedly help test the hypothesized functions of plant autophagy in programmed cell death, vacuole biogenesis, and responses to biotic, abiotic, and nutritional stresses. In this review, we summarize recent progress on these topics and suggest topics for future research, after inspecting common phenotypes of current Arabidopsis atg mutants.     

The emerging role of acetylation in the regulation of autophagy

Autophagy is an evolutionarily conserved catabolic process through which different components of the cells are sequestered into double-membrane cytosolic vesicles called autophagosomes, and fated to degradation through fusion with lysosomes. Autophagy plays a major function in many physiological processes including response to different stress factors, energy homeostasis, elimination of cellular organelles and tissue remodeling during development. Consequently, autophagy is strictly controlled and post-translational modifications such as phosphorylation and ubiquitination have long been associated with autophagy regulation. In contrast, the importance of acetylation in autophagy control has only emerged in the last few years. In this review, we summarize how previously identified histone acetylases and deacetylases modify key autophagic effector proteins, and discuss how this has an impact on physiological and pathological cellular processes.     

Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation

Autophagy is a lysosome-based degradation pathway. During autophagy, lysosomes fuse with autophagosomes to form autolysosomes. Following starvation-induced autophagy, nascent lysosomes are formed from autolysosomal membranes through an evolutionarily conserved cellular process, autophagic lysosome reformation (ALR), which is critical for maintaining lysosome homeostasis. Here we report that clathrin and phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulate ALR. Combining a screen of candidates identified through proteomic analysis of purified ALR tubules, and large-scale RNAi knockdown, we unveiled a tightly regulated molecular pathway that controls lysosome homeostasis, in which clathrin and PtdIns(4,5)P(2) are the central components. Our functional study demonstrates the central role of clathrin and its associated proteins in cargo sorting, phospholipid conversion, initiation of autolysosome tubulation, and proto-lysosome budding during ALR. Our data not only uncover a molecular pathway by which lysosome homeostasis is maintained through the ALR process, but also reveal unexpected functions of clathrin and PtdIns(4,5)P(2) in lysosome homeostasis.     

Don't forget to be picky – selective autophagy of protein aggregates in neurodegenerative diseases

The homeostasis of cells depends on the selective degradation of damaged or superfluous cellular components. Autophagy is the major pathway that recognizes such components, sequesters them in de novo formed autophagosomes and delivers them to lysosomes for degradation. The recognition of specific cargo and the biogenesis of autophagosomes involve a dedicated machinery of autophagy related (ATG) proteins. Intense research over the past decades has revealed insights into the function of autophagy proteins and mechanisms that govern cargo recognition. Other aspects including the molecular mechanisms involved in the onset of human diseases are less well understood. However, autophagic dysfunctions, caused by age related decline in autophagy or mutations in ATG proteins, are directly related to a large number of human pathologies including neurodegenerative disorders. Here, we review most recent discoveries and breakthroughs in selective autophagy and its relationship to neurodegeneration.     

The roles of autophagy in development and stress responses in Arabidopsis thaliana

Autophagy is a dynamic process that involves the recycling process of the degradation of intracellular materials. Over the past decade, our molecular and physiological understanding of plant autophagy has greatly been increased. Most essential autophagic machineries are conserved from yeast to plants. The roles that autophagy-related genes (ATGs) family play in the lifecycle of the Arabidopsis are proved to be similar to that in mammal. Autophagy is activated during certain stages of development, senescence or in response to starvation, or environmental stress in Arabidopsis. In the progression of autophagy, ATGs act as central signaling regulators and could develop sophisticated mechanisms to survive when plants are suffering unfavorable environments. It will facilitate further understanding of the molecular mechanisms of autophagy in plant. In this review, we will discuss recent advances in our understanding of autophagy in Arabidopsis, areas of controversy, and highlight potential future directions in autophagy research.