Regulation Mechanisms and Signaling Pathways of Autophagy

He, Congcong; Klionsky, Daniel J.

doi:10.1146/annurev-genet-102808-114910

Cited by 3,229 publications

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“…Microautophagy is under control of the target of rapamycin (TOR) pathway and has been most fully defined in yeast (Li et al 2012). Conversely, macroautophagy (hereafter referred to as autophagy) is the main autophagic pathway in higher eukaryotes, and is involved both in bulk and selective substrate degradation (He and Klionsky 2009). Macroautophagy substrates are enveloped into a double membrane vesicle, called autophagosomes, which then fuses with the lysosome and releases the substrates for degradation.…”

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“…This linkage allows LC3-PE (or LC3-II) to associate with the membrane of the nascent autophagosome and regulate its size and shape (Xie et al 2008). Once the autophagosome has formed around its substrate, it is delivered to the lysosome, where the cargo is degraded and its components recycled (He and Klionsky 2009).…”

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“…More specifically, autophagy is directly regulated by the nutrient and energy status of the cell and by genes involved in lifespan extension: insulin/IGF-1 and amino acids signaling activate TORC1 and repress autophagy, while the energy sensor AMP-dependent protein kinase (AMPK) can directly activate the Atg1 complex, bypassing TORC1 activity (Jung et al 2009;Kim et al 2011), and the FoxO transcription factor regulates the expression of several autophagy genes in skeletal muscle (Zhao et al 2007;Mammucari et al 2007). Autophagy can also be induced by several cellular stresses, such as ER overload, hypoxia, oxidative stress, and pathogens (He and Klionsky 2009). Because it is induced by virtually all longevity pathways, it is thought that autophagy is one of the beneficial effects of prolongevity interventions.…”

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p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

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124

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

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124

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“…1,12 Furthermore, autophagy is required during periods of starvation or stress due to growth factor deprivation and therefore it has a crucial prosurvival role in cell homeostasis. 12,13 This defines the Janus role of autophagy and its ability to control a wide range of physiological processes, such as starvation, cell differentiation, cell survival, and death. 14 Finally, necroptosis is characterized by the relatively smallest number of regulators.…”

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Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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“…On the basis of the mechanism used for delivery of intracellular cargoes to lysosomes, autophagy can be divided into three types: macroautophagy (MA), microautophagy, and chaperone-mediated autophagy (CMA) [8,9] . Both CMA and MA have been identified in mammals as processes important for damage and diseases of the central nervous system [10] .…”

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Chaperone-mediated autophagy: roles in neuroprotection

et al. 2015

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Chaperone-mediated autophagy (CMA), one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif biochemically related to the pentapeptide KFERQ. Along with the other two lysosomal pathways, macro-and micro-autophagy, CMA is essential for maintaining cellular homeostasis and survival by selectively degrading misfolded, oxidized, or damaged cytosolic proteins. CMA plays an important role in pathologies such as cancer, kidney disorders, and neurodegenerative diseases. Neurons are post-mitotic and highly susceptible to dysfunction of cellular quality-control systems. Maintaining a balance between protein synthesis and degradation is critical for neuronal functions and homeostasis. Recent studies have revealed several new mechanisms by which CMA protects neurons through regulating factors critical for their viability and homeostasis. In the current review, we summarize recent advances in the understanding of the regulation and physiology of CMA with a specifi c focus on its possible roles in neuroprotection.Keywords: chaperone-mediated autophagy; cellular homeostasis; neuroprotection; neuronal death; neurodegenerative disease ·Review· IntroductionMaintaining the balance between protein synthesis and degradation contributes to cellular homeostasis [1][2][3] . The ubiquitin-proteasome system (UPS) and the autophagylysosome pathway (ALP) are major systems present in almost all cell types to mediate the degradation of intracellular proteins into their constitutive amino-acids [4,5] .The UPS is a multi-subunit protease complex that degrades proteins tagged with one or more covalently-bound ubiquitin molecules, and most proteasome substrates are proteins with a short half-life [6,7] .In contrast to the UPS, the ALP is mainly responsible for the degradation of long-lived proteins and organelles.On the basis of the mechanism used for delivery of intracellular cargoes to lysosomes, autophagy can be divided into three types: macroautophagy (MA), microautophagy, and chaperone-mediated autophagy (CMA) [8,9] . Both CMA and MA have been identified in mammals as processes important for damage and diseases of the central nervous system [10] . MA is a bulk degradation system that involves the formation of a double-membrane structure (autophagosome) that sequesters damaged organelles and proteins. The autophagosome acquires the hydrolytic enzymes necessary to degrade its cargo by fusing with lysosomes [11] . Microautophagy traps nonspecifi c cytoplasm inside vesicles via direct invagination of the lysosomal membrane. These vesicles "pinch off" into the lumen and are degraded by lysosomal hydrolases [12] .CMA is the third type of autophagy, and has so far been found only in mammalian cells [13,14] . One of its intrinsic features is the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif related to the pentapeptide KFERQ [15,16] [17][1...

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Regulation Mechanisms and Signaling Pathways of Autophagy

Cited by 3,229 publications

References 174 publications

p62/SQSTM1 at the interface of aging, autophagy, and disease

p62/SQSTM1 at the interface of aging, autophagy, and disease

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Chaperone-mediated autophagy: roles in neuroprotection

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