• 제목/요약/키워드: autophagy

검색결과 465건 처리시간 0.019초

Structure biology of selective autophagy receptors

  • Kim, Byeong-Won;Kwon, Do Hoon;Song, Hyun Kyu
    • BMB Reports
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    • 제49권2호
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    • pp.73-80
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    • 2016
  • Autophagy is a process tightly regulated by various autophagy-related proteins. It is generally classified into non-selective and selective autophagy. Whereas non-selective autophagy is triggered when the cell is under starvation, selective autophagy is involved in eliminating dysfunctional organelles, misfolded and/or ubiquitylated proteins, and intracellular pathogens. These components are recognized by autophagy receptors and delivered to phagophores. Several selective autophagy receptors have been identified and characterized. They usually have some common domains, such as motif, a specific cargo interacting (ubiquitin-dependent or ubiquitin-independent) domain. Recently, structural data of these autophagy receptors has been described, which provides an insight of their function in the selective autophagic process. In this review, we summarize the most up-to-date findings about the structure-function of autophagy receptors that regulates selective autophagy.

Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology

  • Valencia, McNeil;Kim, Sung Rae;Jang, Yeseul;Lee, Sung Hoon
    • Biomolecules & Therapeutics
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    • 제29권6호
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    • pp.605-614
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    • 2021
  • Autophagy is an important degradative pathway that eliminates misfolded proteins and damaged organelles from cells. Autophagy is crucial for neuronal homeostasis and function. A lack of or deficiency in autophagy leads to the accumulation of protein aggregates, which are associated with several neurodegenerative diseases. Compared with non-neuronal cells, neurons exhibit rapid autophagic flux because damaged organelles or protein aggregates cannot be diluted in post-mitotic cells; because of this, these cells exhibit characteristic features of autophagy, such as compartment-specific autophagy, which depends on polarized structures and rapid autophagy flux. In addition, neurons exhibit compartment-specific autophagy, which depends on polarized structures. Neuronal autophagy may have additional physiological roles other than amino acid recycling. In this review, we focus on the characteristics and regulatory factors of neuronal autophagy. We also describe intracellular selective autophagy in neurons and its association with neurodegenerative diseases.

Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot

  • Kwon, Yoojin;Kim, Ji Wook;Jeoung, Jo Ae;Kim, Mi-Sung;Kang, Chanhee
    • Molecules and Cells
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    • 제40권9호
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    • pp.607-612
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    • 2017
  • When mammalian cells and animals face a variety of internal or external stresses, they need to make homeostatic changes so as to cope with various stresses. To this end, mammalian cells are equipped with two critical stress responses, autophagy and cellular senescence. Autophagy and cellular senescence share a number of stimuli including telomere shortening, DNA damage, oncogenic stress and oxidative stress, suggesting their intimate relationship. Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. These seemingly opposite roles of autophagy may reflect a complex picture of autophagic regulation on cellular senescence, including different types of autophagy or a unique spatiotemporal activation of autophagy. Thus, a better understanding of autophagy process will lead us to not only elucidate the conundrum how autophagy plays dual roles in the regulation of cellular senescence but also helps the development of new therapeutic strategies for many human diseases associated with cellular senescence. We address the pro-senescence and anti-senescence roles of autophagy while focusing on the potential mechanistic aspects of this complex relationship between autophagy and cellular senescence.

Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy

  • Jae-Sung Park;Min Ju Lee;Seong Bin Jo;Young Ae Joe
    • Biomolecules & Therapeutics
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    • 제31권1호
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    • pp.1-15
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    • 2023
  • Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.

Lipopolysaccharide (LPS)-Induced Autophagy Is Responsible for Enhanced Osteoclastogenesis

  • Sul, Ok-Joo;Park, Hyun-Jung;Son, Ho-Jung;Choi, Hye-Seon
    • Molecules and Cells
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    • 제40권11호
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    • pp.880-887
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    • 2017
  • We hypothesized that inflammation affects number and activity of osteoclasts (OCs) via enhancing autophagy. Lipopolysaccharide (LPS) induced autophagy, osteoclastogenesis, and cytoplasmic reactive oxygen species (ROS) in bone marrow-derived macrophages that were pre-stimulated with receptor activator of nuclear $factor-{\kappa}B$ ligand. An autophagy inhibitor, 3-methyladenine (3-MA) decreased LPS-induced OC formation and bone resorption, indicating that autophagy is responsible for increasing number and activity of OCs upon LPS stimulus. Knockdown of autophagy-related protein 7 attenuated the effect of LPS on OC-specific genes, supporting a role of LPS as an autophagy inducer in OC. Removal of ROS decreased LPS-induced OC formation as well as autophagy. However, 3-MA did not affect LPS-induced ROS levels, suggesting that ROS act upstream of phosphatidylinositol-4,5-bisphosphate 3-kinase in LPS-induced autophagy. Our results suggest the possible use of autophagy inhibitors targeting OCs to reduce inflammatory bone loss.

Autophagy in Neurodegenerative Diseases: From Mechanism to Therapeutic Approach

  • Nah, Jihoon;Yuan, Junying;Jung, Yong-Keun
    • Molecules and Cells
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    • 제38권5호
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    • pp.381-389
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    • 2015
  • Autophagy is a lysosome-dependent intracellular degradation process that allows recycling of cytoplasmic constituents into bioenergetic and biosynthetic materials for maintenance of homeostasis. Since the function of autophagy is particularly important in various stress conditions, perturbation of autophagy can lead to cellular dysfunction and diseases. Accumulation of abnormal protein aggregates, a common cause of neurodegenerative diseases, can be reduced through autophagic degradation. Recent studies have revealed defects in autophagy in most cases of neurodegenerative disorders. Moreover, deregulated excessive autophagy can also cause neurodegeneration. Thus, healthy activation of autophagy is essential for therapeutic approaches in neurodegenerative diseases and many autophagy-regulating compounds are under development for therapeutic purposes. This review describes the overall role of autophagy in neurodegeneration, focusing on various therapeutic strategies for modulating specific stages of autophagy and on the current status of drug development.

Curcumin-Induced Autophagy Augments Its Antitumor Effect against A172 Human Glioblastoma Cells

  • Lee, Jong-Eun;Yoon, Sung Sik;Moon, Eun-Yi
    • Biomolecules & Therapeutics
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    • 제27권5호
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    • pp.484-491
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    • 2019
  • Glioblastoma is the most aggressive common brain tumor in adults. Curcumin, from Curcuma longa, is an effective antitumor agent. Although the same proteins control both autophagy and cell death, the molecular connections between them are complicated and autophagy may promote or inhibit cell death. We investigated whether curcumin affects autophagy, which regulates curcumin-mediated tumor cell death in A172 human glioblastoma cells. When A172 cells were incubated with $10{\mu}M$ curcumin, autophagy increased in a time-dependent manner. Curcumin-induced cell death was reduced by co-incubation with the autophagy inhibitors 3-methyladenine (3-MA), hydroxychloroquine (HCQ), and LY294002. Curcumin-induced cell death was also inhibited by co-incubation with rapamycin, an autophagy inducer. When cells were incubated under serum-deprived medium, LC3-II amount was increased but the basal level of cell viability was reduced, leading to the inhibition of curcumin-induced cell death. Cell death was decreased by inhibiting curcumin-induced autophagy using small interference RNA (siRNA) of Atg5 or Beclin1. Therefore, curcumin-mediated tumor cell death is promoted by curcumin-induced autophagy, but not by an increase in the basal level of autophagy in rapamycin-treated or serum-deprived conditions. This suggests that the antitumor effects of curcumin are influenced differently by curcumin-induced autophagy and the prerequisite basal level of autophagy in cancer cells.

Autophagy-Is it a preferred route for lifespan extension?

  • Dwivedi, Meenakshi;Ahnn, Joo-Hong
    • BMB Reports
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    • 제42권2호
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    • pp.65-71
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    • 2009
  • Autophagy, which is a process of self eating, has gained interest in the past decade due to its both beneficial and controversial roles in various biological phenomena. The discovery of autophagy genes (ATG) in yeast has led to focused research designed to elucidate the mechanism and regulation of this process. The role of autophagy in a variety of biological phenomena, including human disease, is still the subject of debate. However, recent findings suggest that autophagy is a highly regulated process with both beneficial and negative effects. Indeed, studies conducted using various model organisms have demonstrated that increased autophagy leads to an extended lifespan. Despite these findings, it is still unknown if all pathways leading to extended lifespan converge at the process of autophagy or not. Here, an overview of modern developments related to the process of autophagy, its regulation and the molecular machinery involved is presented. In addition, this review focuses on one of the beneficial aspects of autophagy, its role in lifespan regulation.

Quantitative and qualitative analysis of autophagy flux using imaging

  • Kim, Suree;Choi, Soohee;Kang, Dongmin
    • BMB Reports
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    • 제53권5호
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    • pp.241-247
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    • 2020
  • As an intracellular degradation system, autophagy is an essential and defensive cellular program required for cell survival and cellular metabolic homeostasis in response to various stresses, such as nutrient deprivation and the accumulation of damaged organelles. In general, autophagy flux consists of four steps: (1) initiation (formation of phagophore), (2) maturation and completion of autophagosome, (3) fusion of autophagosomes with lysosomes (formation of autolysosome), and (4) degradation of intravesicular components within autolysosomes. The number of genes and reagents that modulate autophagy is increasing. Investigation of their effect on autophagy flux is critical to understanding the roles of autophagy in many physiological and pathological processes. In this review, we summarize and discuss ways to analyze autophagy flux quantitatively and qualitatively with the use of imaging tools. The suggested imaging method can help estimate whether each modulator is an inhibitor or a promoter of autophagy and elucidate the mode of action of specific genes and reagents on autophagy processes.

Autophagy in neutrophils

  • Shrestha, Sanjeeb;Lee, Jae Man;Hong, Chang-Won
    • The Korean Journal of Physiology and Pharmacology
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    • 제24권1호
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    • pp.1-10
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    • 2020
  • Autophagy is a highly conserved intracellular degradation and energy-recycling mechanism that contributes to the maintenance of cellular homeostasis. Extensive researches over the past decades have defined the role of autophagy innate immune cells. In this review, we describe the current state of knowledge regarding the role of autophagy in neutrophil biology and a picture of molecular mechanism underlying autophagy in neutrophils. Neutrophils are professional phagocytes that comprise the first line of defense against pathogen. Autophagy machineries are highly conserved in neutrophils. Autophagy is not only involved in generalized function of neutrophils such as differentiation in bone marrow but also plays crucial role effector functions of neutrophils such as granule formation, degranulation, neutrophil extracellular traps release, cytokine production, bactericidal activity and controlling inflammation. This review outlines the current understanding of autophagy in neutrophils and provides insight towards identification of novel therapeutics targeting autophagy in neutrophils.