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The Atg12-Atg5 conjugate, which is formed by an ubiquitin-like conjugation system, is essential to autophagosome formation, a central event in autophagy. Despite its importance, the molecular mechanism of the Atg12-Atg5 conjugate ...
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The Atg12-Atg5 conjugate, which is formed by an ubiquitin-like conjugation system, is essential to autophagosome formation, a central event in autophagy. Despite its importance, the molecular mechanism of the Atg12-Atg5 conjugate formation has not been elucidated. Here, we report the solution and crystal structures of Atg10 and Atg5 homologs from Kluyveromyces marxianus (Km), a thermotolerant yeast. KmAtg10 comprises an E2-core fold with characteristic accessories, including two β strands, whereas KmAtg5 has two ubiquitin-like domains and a helical domain. The nuclear magnetic resonance experiments, mutational analyses, and crosslinking experiments showed that KmAtg10 directly recognizes KmAtg5, especially its C-terminal ubiquitin-like domain, by its characteristic two β strands. Kinetic analysis suggests that Tyr56 and Asn114 of KmAtg10 may place the side chain of KmAtg5 Lys145 into the optimal orientation for its conjugation eaction with Atg12. These structural features enable Atg10 to mediate the formation of the Atg12-Atg5 conjugate without a specific E3 enzyme.
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Autophagy, an intracellular degradation process highly conserved from yeast to humans, is viewed as an important defence mechanism to clear intracellular bacteria. However, recent work has shown that autophagy may have different r...
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Autophagy, an intracellular degradation process highly conserved from yeast to humans, is viewed as an important defence mechanism to clear intracellular bacteria. However, recent work has shown that autophagy may have different roles during different bacterial infections that restrict bacterial replication (antibacterial autophagy), act in cell autonomous signalling (non-bacterial autophagy) or support bacterial replication (pro-bacterial autophagy). This review will focus on newfound interactions of autophagy and pathogenic bacteria,highlighting that, in addition to delivering bacteria to the lysosome, autophagy responding to bacterial invasion may have a much broader role in mediating disease outcome.
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Autophagy is a stress response that is upregulated in response to signals such as starvation, growth factor deprivation, endoplasmic reticulum stress, and pathogen infection. Defects in this pathway are the underlying cause of a n...
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Autophagy is a stress response that is upregulated in response to signals such as starvation, growth factor deprivation, endoplasmic reticulum stress, and pathogen infection. Defects in this pathway are the underlying cause of a number of diseases, including metabolic aberrations, infectious diseases, and cancer, which are closely related to hepatic disorders. To date, more than 30 human ATG (autophagy) genes have been reported to regulate autophagosome formation. In this review, we summarize the current understanding of how ATG proteins behave during autophagosome formation in both non-selective and selective autophagy.
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Lys05 is a previously undescribed dimeric chloroquine which more potently accumulates in the lysosome and blocks autophagy compared with HCQ. Lys05 produced more potent antitumor activity as a single agent both in vitro and in viv...
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Lys05 is a previously undescribed dimeric chloroquine which more potently accumulates in the lysosome and blocks autophagy compared with HCQ. Lys05 produced more potent antitumor activity as a single agent both in vitro and in vivo in multiple human cancer cell lines and xenograft models compared with HCQ. Initial structure-activity relationship studies demonstrated that the increased activity associated with Lys05 was due to the bivalent aminoquinoline rings, C7-Chlorine, and a short triamine linker. While lower doses of Lys05 were well tolerated and associated with antitumor activity, at the highest dose tested, Lys05 produced Paneth cell dysfunction and intestinal toxicity, similar to what can be observed in mice and humans with genetic defects in the autophagy gene ATG16L1. Lys05 is therefore a new lysosomal autophagy inhibitor that has potential to be developed further into a drug for cancer and other medical applications.
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Autophagy is a complex, physiological process devoted to degrade and recycle cellular components. Proteins and organelles are first phagocytized by autophagosomes, then digested in lysosomes, and finally recycled to be utilized ag...
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Autophagy is a complex, physiological process devoted to degrade and recycle cellular components. Proteins and organelles are first phagocytized by autophagosomes, then digested in lysosomes, and finally recycled to be utilized again during cellular metabolism. Moreover, autophagy holds an important role in the physiopathology of several diseases. In cancer, excellent works demonstrated the dual functions of autophagy in tumour biology: autophagy activation can promote cancer cells survival (protective autophagy), or contribute to cancer cell death (cytotoxic/nonprotective autophagy). A better understanding of the dichotomy roles of autophagy in cancer biology can help to identify or design new drugs able to induce/enhance (or block) autophagic flux. These features will necessary be tissue-dependent and confined to a specific time of treatment. The intent of this review is to focus on the different potentialities of autophagy inducers in cancer prevention versus therapy in order to elicit a desirable clinical response. Few promising synthetic and natural compounds have been identified and the pros and cons of their role in autophagy regulation is reviewed here. In the complex framework of autophagy modulation, "connecting the dots" is not a simple work and the lack of clinical studies further complicates the scenario, but the final goal to obtain clinically relevant autophagy inducers can reveal an unexpected landscape.
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Autophagy is an evolutionarily conserved process for the degradation of redundant or damaged cellular material by means of a lysosome-dependent mechanism, contributing to cell homeostasis and survival. Autophagy plays a multifacet...
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Autophagy is an evolutionarily conserved process for the degradation of redundant or damaged cellular material by means of a lysosome-dependent mechanism, contributing to cell homeostasis and survival. Autophagy plays a multifaceted and context-dependent role in cancer initiation, maintenance, and progression; it has a tumor suppressive role in the absence of disease and is upregulated in cancer cells to meet their elevated metabolic demands. Autophagy represents a promising but challenging target in cancer treatment. Green tea is a widely used beverage with healthy effects on several diseases, including cancer. The bioactive compounds of green tea are mainly catechins, and epigallocatechin-gallate (EGCG) is the most abundant and biologically active among them. In this review, evidence of autophagy modulation and anti-cancer effects induced by EGCG treatment in experimental cancer models is presented. Reviewed articles reveal that EGCG promotes cytotoxic autophagy often through the inactivation of PI3K/Akt/mTOR pathway, resulting in apoptosis induction. EGCG pro-oxidant activity has been postulated to be responsible for its anti-cancer effects. In combination therapy with a chemotherapy drug, EGCG inhibits cell growth and the drug-induced pro-survival autophagy. The selected studies rightly claim EGCG as a valuable agent in cancer chemoprevention.
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Recent evidence suggests that autophagy is a governed catabolic framework enabling the recycling of nutrients from injured organelles and other cellular constituents via a lysosomal breakdown. This mechanism has been associated wi...
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Recent evidence suggests that autophagy is a governed catabolic framework enabling the recycling of nutrients from injured organelles and other cellular constituents via a lysosomal breakdown. This mechanism has been associated with the development of various pathologic conditions, including cancer and neurological disorders; however, recently updated studies have indicated that autophagy plays a dual role in cancer, acting as a cytoprotective or cytotoxic mechanism. Numerous preclinical and clinical investigations have shown that inhibiting autophagy enhances an anticancer medicine's effectiveness in various malignancies. Autophagy antagonists, including chloroquine and hydroxychloroquine, have previously been authorized in clinical trials, encouraging the development of medication-combination therapies targeting the autophagic processes for cancer. In this review, we provide an update on the recent research examining the anticancer efficacy of combining drugs that activate cytoprotective autophagy with autophagy inhibitors. Additionally, we highlight the difficulties and progress toward using cytoprotective autophagy targeting as a cancer treatment strategy. Importantly, we must enable the use of suitable autophagy inhibitors and coadministration delivery systems in conjunction with anticancer agents. Therefore, this review briefly summarizes the general molecular process behind autophagy and its bifunctional role that is important in cancer suppression and in encouraging tumor growth and resistance to chemotherapy and metastasis regulation. We then emphasize how autophagy and cancer cells interacting with one another is a promising therapeutic target in cancer treatment.
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Two primary forms of autophagy have been identified in the field of cancer therapy based on their apparent functions in the tumor cell; these are the cytoprotective form that could, in theory, be inhibited for the purpose of sensi...
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Two primary forms of autophagy have been identified in the field of cancer therapy based on their apparent functions in the tumor cell; these are the cytoprotective form that could, in theory, be inhibited for the purpose of sensitization to radiation and chemotherapeutic drugs and the "cytotoxic" form that either mediates or contributes to the actions of these treatment modalities. Surprisingly, to date, no clear-cut biochemical or molecular characteristics have been identified that might serve to distinguish between these two forms. In this commentary, we develop the concept of an additional form of autophagy that is nonprotective in that its inhibition neither sensitizes the tumor cell to exogenous stress (again, chemotherapy or radiation) nor protects the cell from the impact of these treatments. This form of autophagy also fails to exhibit any characteristics that might distinguish it from the cytoprotective and/or cytotoxic forms of autophagy. However, the existence of nonprotective autophagy is of potential significance in that it contributes to the challenge of predicting when the strategy of autophagy suppression might prove to have therapeutic benefit in the clinical treatment of cancer.
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Autophagy is responsible for degradation of non-essential or damaged cellular constituents and damaged organelles. The autophagy pathway maintains efficient cellular metabolism and reduces cellular stress by removing additional an...
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Autophagy is responsible for degradation of non-essential or damaged cellular constituents and damaged organelles. The autophagy pathway maintains efficient cellular metabolism and reduces cellular stress by removing additional and pathogenic components. Dysfunctional autophagy underlies several diseases. Thus, several research groups have worked toward elucidating key steps in this pathway. Autophagy can be studied by animal modeling, chemical modulators, and in vitro disease modeling with induced pluripotent stem cells (iPSC) as a loss-of-function platform. The introduction of iPSC technology, which has the capability to maintain the genetic background, has facilitated in vitro modeling of some diseases. Furthermore, iPSC technology can be used as a platform to study defective cellular and molecular pathways during development and unravel novel steps in signaling pathways of health and disease. Different studies have used iPSC technology to explore the role of autophagy in disease pathogenesis which could not have been addressed by animal modeling or chemical inducers/inhibitors. In this review, we discuss iPSC models of autophagy-associated disorders where the disease is caused due to mutations in autophagy-related genes. We classified this group as "primary autophagy induced defects (PAID)". There are iPSC models of diseases in which the primary cause is not dysfunctional autophagy, but autophagy is impaired secondary to disease phenotypes. We call this group "secondary autophagy induced defects (SAID)" and discuss them.
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Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneerin...
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Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneering and groundbreaking research that centers on delineating the role of autophagy in cancer initiation, proliferation and metastasis. First, we discuss the autophagy-related (ATG) proteins and their respective roles in the de novo formation of autophagosomes and the subsequent delivery of cargo to the lysosome for recycling. Next, we touch upon the history of cancer research that centers upon ATG proteins and regulatory mechanisms that control an appropriate autophagic response and how these are altered in the diseased state. Then, we discuss the various discoveries that led to the idea of autophagy as a double-edged sword when it comes to cancer therapy. This review also briefly narrates how different types of autophagy-selective macroautophagy and chaperone-mediated autophagy, have been linked to different cancers. Overall, these studies build upon a steadfast trajectory that aims to solve the monumentally daunting challenge of finding a cure for many types of cancer by modulating autophagy either through inhibition or induction.
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