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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
TRPML3 also regulates the autophagic pathway. TRPML3 overexpression increases autophagosome accumulation whereas TRPML3 down-regulation reduces autophagosomes (Kim et al., 2009; Martina et al., 2009; Scotto Rosato et al., 2019). Mechanistically, upon nutrient starvation, TRPML3 may interact with GATE16, a mammalian ATG8 homologue, but not LC3B to facilitate autophagosome formation (Choi and Kim, 2014). TRPML3 regulating autophagy is also under the control of palmitoylation (Kim et al., 2019). Although no direct evidence suggesting a role of TRPML2 in autophagy, TRPML2-mediated Ca2+ release may activate TFEB-dependent gene expression to regulate autophagy pathway in some specific types of cells (Ma et al., 2018).
Mitochondrial Dysfunction, Immune Systems, Their Diseases, and Possible Treatments
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Elise Jacquin, Eric Hervouet, Michaël Boyer-Guittaut
Autophagy is a cellular catabolic process, described for the first time in the 1960s by Christian de Duve.68 This field attracted some important interest since the 1990s with the characterization of this mechanism in yeast and the discovery of the homolog proteins in humans leading to the attribution of the Nobel Prize to Yoshinori Ohsumi in 2016 for its contribution to the development of the autophagy field.69 Autophagy is an intracellular degradation process leading to the formation of an intracellular double-membrane vesicle, called autophagosome, which engulfs part of the cytoplasm (soluble proteins, protein aggregates or even organelles) and then fuses with the lysosome to induce the degradation of this vesicle and its content. This process is highly regulated by more than 40 ATG (AuTophaGy-related) proteins and can be induced by numerous stress conditions such as starvation, hypoxia, oxidative stress, chemical drugs ? For years, this process has been described as non-selective and the complement of the proteasome since it can degrade aggregates or organelles while proteasome only proteolize soluble proteins. But, during the last decade, a selective function of autophagy has emerged. Indeed, several teams have described specific adapters (P62/SQSTM1, NBR1, OPTN, NDP52, NIX, BNIP3/3L) which interact with specific cargo (the aggregate or organelle to degrade) and a member of the ATG8 family (LC3 or GABARAP family) to induce the specific recruitment of the cargo into the autophagosome leading to its degradation. This selective process has been named according to the cargo degraded: aggrephagy, xenophagy, ribophagy, pexophagy, nucleophagy, glycophagy, mitophagy.
Mitochondrial Oxidative Stress in Aging and Healthspan
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Additional evidence to support the association between autophagy and aging is shown by antiaging intervention studies (section Potential Interventions). Many interventions that have been shown to extend life span, including mammalian target of rapamycin (mTOR) inhibition by rapamycin49 or calorie restriction (CR)50 and Sirtuin activators51 are mediated through enhanced autophagy (Figure 21.3c).32,45,52–54 Similar to CR, inhibition of mTORC1 by rapamycin is well documented to extend life span in invertebrate models of aging, including flies,55 worms,56,57 and yeast,58,59 as well as in mice.49,60 In yeast and Drosophila, the life span extension by rapamycin was inhibited by deletion or silencing of Atg1, Atg7, or Atg5,53,54 indicating that enhanced autophagy is required for the life span extension benefit of mTORC1 inhibition. Sirtuins are class III histone deacetylases that deacetylate (activate) numerous transcription factors, cofactors, histones, and enzymes in response to metabolic stress using NAD+ as a cofactor. Dependent on cytoplasmic or mitochondrial NAD+, sirtuins act as a “sensor” protein for nutrition and energy balance.61,62 Sirtuins deacetylations of downstream pathways counteract the pathogenic mechanisms underlying aging and longevity as well as several age-related diseases, including diabetes, cardiovascular disease, cancer, inflammatory diseases, and neurodegenerative conditions.63 For example, Sirt1 has been shown to affect regulators of autophagy and many autophagy-related genes, including Atg5, Atg7, and Atg8.64 Sirt1 life span extension effect is also dependent on autophagy, as deletion of Beclin-1 (Atg6) which suppressed the induction of autophagy by Sirt, abolish its life span extension effect.52 Furthermore, several other interventions improving protein quality control have also been shown to improve health and aging in invertebrate and mammalian models.32,39,45,46
Autophagy-dependent ferroptosis is involved in the development of endometriosis
Published in Gynecological Endocrinology, 2023
Hui Li, Huadi Yang, Shenyi Lu, Xinyan Wang, Xinhe Shi, Peiyu Mao
Autophagy is a cellular degradation process that removes and recycles damaged proteins and organelles through the lysosomal machinery. Initiated by the formation of a phagophore, a double-membrane structure, autophagy is mediated by various Atg proteins that control the expansion of the phagophore, resulting in an autophagosome. Several Atgs are associated with autophagy, among which LC3 and Beclin1 are significant factors [7]. LC3, a gene homologous to the Atg8 autophagy-related gene in yeast, is a unique marker of autophagosomes, and its expression level directly signifies the degree of autophagy [8]. Beclin1 also referred to as BECN 1, is an autophagy-specific gene, a tumor suppressor gene related to autophagy, and a direct autophagy regulator in mammals [9]. The autophagosome then merges with a lysosome, leading to the degradation and recycling of its content [10,11]. This process plays a pivotal role in maintaining cellular homeostasis. Dysregulation of autophagy, as has been suggested in the context of EMS, may promote the survival and proliferation of ectopic endometrial cells [3]. EMS exhibits numerous tumor disease traits, including metastasis, implantation, and recurrence [12,13]. Various studies have reported a link between autophagy and several malignant tumors. For instance, a decrease in autophagy activity has been associated with the onset and progression of various cancers, including pancreatic, breast, cervical squamous cell, colon, and ovarian cancer, indicating a strong correlation between the abnormal expression of autophagy-related genes and tumor development [14,15].
Autophagy regulation of ATG13 and ATG27 on biofilm formation and antifungal resistance in Candida albicans
Published in Biofouling, 2022
Siqi Liu, Liuliu Jiang, Haochen Miao, Ying Lv, Qinqin Zhang, Ming Ma, Wei Duan, Yun Huang, Xin Wei
GFP-ATG8 was used as a molecular indicator to microscopically observe the autophagic process in C. albicans. ATG8 is a ubiquitin-like protein that conjugates with phosphatidylethanolamine (PE), a key autophagy-related protein associated with the development of autophagosomes. The production of ATG8 represents autophagic activity inside the yeast (Nair et al. 2011; Sora et al. 2020). Most ATG8 is conjugated to PE and is recruited to the phagophore assembly site at the inner and outer phagophore membranes before autophagy. Following the recruitment to phagophore assembly site and autophagosome development, ATG8-PE is delivered to the vacuole and degraded by vacuolar proteases (Liu et al. 2014). GFP-ATG8 exhibits the same behavior as ATG8-PE and is therefore used to follow the phagophore or autophagosome in vivo. When GFP-ATG8 enters the vacuole, its proteolysis of GFP-ATG8 degrades and releases an intact GFP moiety. Because GFP is relatively resistant to degradation, the accumulation of GFP in the vacuole represents autophagic processing of ATG8 and reflects cellular autophagic activity (Zhang et al. 2020).
Secretory autophagy: a turn key for understanding AMD pathology and developing new therapeutic targets?
Published in Expert Opinion on Therapeutic Targets, 2022
Janusz Blasiak, Kai Kaarniranta
The core set of proteins used for autophagosome synthesis consists of four functional groups: the Unc-51 like autophagy activating kinase 1 (ULK1) complex, class III phosphatidylinositol 3-kinase (PI3KC3), two ubiquitin-like proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related protein 12 (ATG12), and the membrane cycling protein, ATG9 [10]. Autophagosome formation starts with nucleation of an isolation membrane/phagophore and activation of the ULK1 complex, recruiting ATG proteins. ULK1 stimulates PI3KC3 activity through the phosphorylation of ATG14 and Beclin-1 (BCN1), which supplements the membrane in phosphatidylinositol 3-phosphate (PI3P) and promotes binding of proteins containing the FYVE domain. ATG9 moves to the phagophore to supply lipids for its expansion. ATG8 is incorporated into the phagophore through an E3-like reaction in which the ATG12/ATG5/ATG16 complex conjugates ATG8 to phosphatidylethanolamine (PE). In mammals, the ATG8 family contains six members, including the LC3 and γ-aminobutyric acid receptor associated protein (GABARAP) subfamilies. The lipidation of mammalian ATG8s relies on the two ubiquitin-like conjugation systems [11].