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1.
Autophagy ; 20(7): 1471-1472, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38744436

RESUMO

The destination of a damaged lysosome is either being repaired if the damage is small or degraded through a lysosome-specific macroautophagy/autophagy pathway named lysophagy when the damage is too extensive to repair. Even though previous studies report lumenal glycan exposure during lysosome damage as a signal to trigger lysophagy, it is possibly beneficial for cells to initiate lysophagy earlier than membrane rupture. In a recently published article, Gahlot et al. determined that SPART/SPG20 senses lipid-packing defects and recruits and activates the ubiquitin ligase ITCH, which labels damaged lysosomes with ubiquitin chains to initiate lysophagy.


Assuntos
Autofagia , Lisossomos , Lisossomos/metabolismo , Humanos , Autofagia/fisiologia , Animais , Macroautofagia/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Modelos Biológicos , Ubiquitina/metabolismo
2.
J Cell Sci ; 137(9)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38752931

RESUMO

Peroxisomes are highly plastic organelles that are involved in several metabolic processes, including fatty acid oxidation, ether lipid synthesis and redox homeostasis. Their abundance and activity are dynamically regulated in response to nutrient availability and cellular stress. Damaged or superfluous peroxisomes are removed mainly by pexophagy, the selective autophagy of peroxisomes induced by ubiquitylation of peroxisomal membrane proteins or ubiquitin-independent processes. Dysregulated pexophagy impairs peroxisome homeostasis and has been linked to the development of various human diseases. Despite many recent insights into mammalian pexophagy, our understanding of this process is still limited compared to our understanding of pexophagy in yeast. In this Cell Science at a Glance article and the accompanying poster, we summarize current knowledge on the control of mammalian pexophagy and highlight which aspects require further attention. We also discuss the role of ubiquitylation in pexophagy and describe the ubiquitin machinery involved in regulating signals for the recruitment of phagophores to peroxisomes.


Assuntos
Peroxissomos , Ubiquitinação , Peroxissomos/metabolismo , Humanos , Animais , Autofagia , Macroautofagia , Mamíferos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética
3.
J Cell Biol ; 223(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38573225

RESUMO

Autophagy serves as a stress response pathway by mediating the degradation of cellular material within lysosomes. In autophagy, this material is encapsulated in double-membrane vesicles termed autophagosomes, which form from precursors referred to as phagophores. Phagophores grow by lipid influx from the endoplasmic reticulum into Atg9-positive compartments and local lipid synthesis provides lipids for their expansion. How phagophore nucleation and expansion are coordinated with lipid synthesis is unclear. Here, we show that Faa1, an enzyme activating fatty acids, is recruited to Atg9 vesicles by directly binding to negatively charged membranes with a preference for phosphoinositides such as PI3P and PI4P. We define the membrane-binding surface of Faa1 and show that its direct interaction with the membrane is required for its recruitment to phagophores. Furthermore, the physiological localization of Faa1 is key for its efficient catalysis and promotes phagophore expansion. Our results suggest a positive feedback loop coupling phagophore nucleation and expansion to lipid synthesis.


Assuntos
Autofagossomos , Ácidos Graxos , Macroautofagia , Autofagia , Ácidos Graxos/metabolismo , Retroalimentação , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo
4.
Cell Rep ; 43(5): 114131, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38656870

RESUMO

Atg8 paralogs, consisting of LC3A/B/C and GBRP/GBRPL1/GATE16, function in canonical autophagy; however, their function is controversial because of functional redundancy. In innate immunity, xenophagy and non-canonical single membranous autophagy called "conjugation of Atg8s to single membranes" (CASM) eliminate bacteria in various cells. Previously, we reported that intracellular Streptococcus pneumoniae can induce unique hierarchical autophagy comprised of CASM induction, shedding, and subsequent xenophagy. However, the molecular mechanisms underlying these processes and the biological significance of transient CASM induction remain unknown. Herein, we profile the relationship between Atg8s, autophagy receptors, poly-ubiquitin, and Atg4 paralogs during pneumococcal infection to understand the driving principles of hierarchical autophagy and find that GATE16 and GBRP sequentially play a pivotal role in CASM shedding and subsequent xenophagy induction, respectively, and LC3A and GBRPL1 are involved in CASM/xenophagy induction. Moreover, we reveal ingenious bacterial tactics to gain intracellular survival niches by manipulating CASM-xenophagy progression by generating intracellular pneumococci-derived H2O2.


Assuntos
Família da Proteína 8 Relacionada à Autofagia , Streptococcus pneumoniae , Animais , Camundongos , Autofagia , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Macroautofagia , Proteínas Associadas aos Microtúbulos/metabolismo , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/metabolismo , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/metabolismo
5.
Autophagy ; 20(7): 1559-1576, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38522078

RESUMO

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors.Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.


Assuntos
Ansiedade , Macroautofagia , Neuralgia , Neurônios , Córtex Pré-Frontal , Animais , Neuralgia/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Neurônios/metabolismo , Masculino , Macroautofagia/fisiologia , Ratos Sprague-Dawley , Comportamento Animal , Dor Crônica/metabolismo , Autofagia/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Hiperalgesia
6.
Physiol Rep ; 12(5): e15966, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38444056

RESUMO

Previous studies revealed a controversial role of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC1-regulated macroautophagy in isoproterenol (ISO)-induced cardiac injury. Here we investigated the role of mTORC1 and potential underlying mechanisms in ISO-induced cardiomyocyte necrosis. Two consecutive daily injections of ISO (85 mg/kg, s.c.) or vehicle control (CTL) were administered to C57BL/6J mice with or without rapamycin (RAP, 5 mg/kg, i.p.) pretreatment. Western blot analyses showed that myocardial mTORC1 signaling and the RIPK1-RIPK3-MLKL necroptotic pathway were activated, mRNA expression analyses revealed downregulation of representative TFEB target genes, and Evan's blue dye uptake assays detected increased cardiomyocyte necrosis in ISO-treated mice. However, RAP pretreatment prevented or significantly attenuated the ISO-induced cardiomyocyte necrosis, myocardial inflammation, downregulation of TFEB target genes, and activation of the RIPK1-RIPK3-MLKL pathway. LC3-II flux assays confirmed the impairment of myocardial autophagic flux in the ISO-treated mice. In cultured neonatal rat cardiomyocytes, mTORC1 signaling was also activated by ISO, and inhibition of mTORC1 by RAP attenuated ISO-induced cytotoxicity. These findings suggest that mTORC1 hyperactivation and resultant suppression of macroautophagy play a major role in the induction of cardiomyocyte necroptosis by catecholamine surges, identifying mTORC1 inhibition as a potential strategy to treat heart diseases with catecholamine surges.


Assuntos
Catecolaminas , Miócitos Cardíacos , Animais , Camundongos , Ratos , Camundongos Endogâmicos C57BL , Macroautofagia , Necroptose , Isoproterenol/toxicidade , Alvo Mecanístico do Complexo 1 de Rapamicina , Necrose
7.
Mol Cell ; 84(8): 1556-1569.e10, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38503285

RESUMO

Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane. Detection occurs via sensory amphipathic helices in SPG20 before rupture of the membrane. If lipid-packing defects are extensive, such as during lipid peroxidation, SPG20 recruits and activates ITCH, which marks the damaged lysosome with lysine-63-linked ubiquitin chains to initiate lysophagy and thus triages the lysosome for destruction. With SPG20 being linked to neurodegeneration, these findings highlight the relevance of a coordinated lysosomal damage response for cellular homeostasis.


Assuntos
Lisossomos , Macroautofagia , Humanos , Autofagia/fisiologia , Membranas Intracelulares/metabolismo , Lipídeos , Lisossomos/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismo
8.
Cells ; 13(6)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38534345

RESUMO

In eukaryotes, targeting intracellular components for lysosomal degradation by autophagy represents a catabolic process that evolutionarily regulates cellular homeostasis. The successful completion of autophagy initiates the engulfment of cytoplasmic materials within double-membrane autophagosomes and subsequent delivery to autolysosomes for degradation by acidic proteases. The formation of autolysosomes relies on the precise fusion of autophagosomes with lysosomes. In recent decades, numerous studies have provided insights into the molecular regulation of autophagosome-lysosome fusion. In this review, an overview of the molecules that function in the fusion of autophagosomes with lysosomes is provided. Moreover, the molecular mechanism underlying how these functional molecules regulate autophagosome-lysosome fusion is summarized.


Assuntos
Autofagossomos , Autofagia , Animais , Autofagossomos/metabolismo , Autofagia/fisiologia , Macroautofagia , Homeostase , Lisossomos/metabolismo , Mamíferos
9.
Math Biosci Eng ; 21(2): 2407-2431, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38454689

RESUMO

BACKGROUND: Aggrephagy is a lysosome-dependent process that degrades misfolded protein condensates to maintain cancer cell homeostasis. Despite its importance in cellular protein quality control, the role of aggrephagy in glioma remains poorly understood. OBJECTIVE: To investigate the expression of aggrephagy-related genes (ARGs) in glioma and in different cell types of gliomas and to develop an ARGs-based prognostic signature to predict the prognosis, tumor microenvironment, and immunotherapy response of gliomas. METHODS: ARGs were identified by searching the Reactome database. We developed the ARGs-based prognostic signature (ARPS) using data from the Cancer Genome Atlas (TCGA, n = 669) by Lasso-Cox regression. We validated the robustness of the signature in clinical subgroups and CGGA cohorts (n = 970). Gene set enrichment analysis (GSEA) was used to identify the pathways enriched in ARPS subgroups. The correlations between ARGs and macrophages were also investigated at single cell level. RESULTS: A total of 44 ARGs showed heterogeneous expression among different cell types of gliomas. Five ARGs (HSF1, DYNC1H1, DYNLL2, TUBB6, TUBA1C) were identified to develop ARPS, an independent prognostic factor. GSEA showed gene sets of patients with high-ARPS were mostly enriched in cell cycle, DNA replication, and immune-related pathways. High-ARPS subgroup had higher immune cell infiltration states, particularly macrophages, Treg cells, and neutrophils. APRS had positive association with tumor mutation burden (TMB) and immunotherapy response predictors. At the single cell level, we found ARGs correlated with macrophage development and identified ARGs-mediated macrophage subtypes with distinct communication characteristics with tumor cells. VIM+ macrophages were identified as pro-inflammatory and had higher interactions with malignant cells. CONCLUSION: We identified a novel signature based on ARGs for predicting glioma prognosis, tumor microenvironment, and immunotherapy response. We highlight the ARGs-mediated macrophages in glioma exhibit classical features.


Assuntos
Glioma , Macrófagos Associados a Tumor , Humanos , Macroautofagia , Sequência de Bases , Glioma/genética , Análise de Sequência de RNA , Microambiente Tumoral
10.
Autophagy ; 20(6): 1457-1458, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38348842

RESUMO

The lysosomal degradation of the endoplasmic reticulum (ER), known as "reticulophagy", is important for protein quality control and organelle turnover. Here we present a noncanonical reticulophagy occurring at ER exit sites (ERESs) induced by the misfolded SERPINA1/α1-antitrypsin (AAT) mutant, Z-AAT. The accumulation of Z-AAT arrests ER-to-Golgi transport, and recruits V-ATPase and ATG16L1 to mediate LC3C decoration of ERESs. Consequently, the receptor RETREG1/FAM134B-2 is recruited by lipidated LC3C to initiate reticulophagy. Furthermore, the blockade of ER export acts as a universal signal to activate reticulophagy mediated by the V-ATPase-ATG16L1-LC3C axis. This study sheds light on the mechanism of how ERESs switch from ER export to reticulophagy for quality control.


Assuntos
Proteínas Relacionadas à Autofagia , Retículo Endoplasmático , Proteínas Associadas aos Microtúbulos , ATPases Vacuolares Próton-Translocadoras , Retículo Endoplasmático/metabolismo , Humanos , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Complexo de Golgi/metabolismo , Autofagia/fisiologia , alfa 1-Antitripsina/metabolismo , Animais , Proteínas de Membrana/metabolismo , Lisossomos/metabolismo , Macroautofagia/fisiologia , Transdução de Sinais , Peptídeos e Proteínas de Sinalização Intracelular
11.
Stem Cell Reports ; 19(3): 366-382, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38335961

RESUMO

Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to clear damaged lysosomes and have reduced viability. Lysosomes in mutant motor neurons have increased pH compared with wild-type cells. The clearance of damaged lysosomes involves UBXD1-p97 interaction, which is disrupted in mutant motor neurons. Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.


Assuntos
Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Esclerose Lateral Amiotrófica/genética , Macroautofagia , Neurônios Motores , Mutação
12.
Cell Commun Signal ; 22(1): 142, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383392

RESUMO

BACKGROUND: Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown. METHODS: To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion. RESULTS: This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation. CONCLUSIONS: Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger's syndrome and ageing.


Assuntos
Cálcio , Macroautofagia , Espécies Reativas de Oxigênio/metabolismo , Cálcio/metabolismo , Catalase/metabolismo , Estresse Oxidativo , Autofagia/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
13.
Cell Mol Gastroenterol Hepatol ; 17(6): 1007-1024, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38336172

RESUMO

BACKGROUND & AIMS: In the classic form of α1-antitrypsin deficiency (ATD), the misfolded α1-antitrypsin Z (ATZ) variant accumulates in the endoplasmic reticulum (ER) of liver cells. A gain-of-function proteotoxic mechanism is responsible for chronic liver disease in a subgroup of homozygotes. Proteostatic response pathways, including conventional endoplasmic reticulum-associated degradation and autophagy, have been proposed as the mechanisms that allow cellular adaptation and presumably protection from the liver disease phenotype. Recent studies have concluded that a distinct lysosomal pathway called endoplasmic reticulum-to-lysosome completely supplants the role of the conventional macroautophagy pathway in degradation of ATZ. Here, we used several state-of-the-art approaches to characterize the proteostatic responses more fully in cellular systems that model ATD. METHODS: We used clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genome editing coupled to a cell selection step by fluorescence-activated cell sorter to perform screening for proteostasis genes that regulate ATZ accumulation and combined that with selective genome editing in 2 other model systems. RESULTS: Endoplasmic reticulum-associated degradation genes are key early regulators and multiple autophagy genes, from classic as well as from ER-to-lysosome and other newly described ER-phagy pathways, participate in degradation of ATZ in a manner that is temporally regulated and evolves as ATZ accumulation persists. Time-dependent changes in gene expression are accompanied by specific ultrastructural changes including dilation of the ER, formation of globular inclusions, budding of autophagic vesicles, and alterations in the overall shape and component parts of mitochondria. CONCLUSIONS: Macroautophagy is a critical component of the proteostasis response to cellular ATZ accumulation and it becomes more important over time as ATZ synthesis continues unabated. Multiple subtypes of macroautophagy and nonautophagic lysosomal degradative pathways are needed to respond to the high concentrations of misfolded protein that characterizes ATD and these pathways are attractive candidates for genetic variants that predispose to the hepatic phenotype.


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático , Lisossomos , Macroautofagia , Proteostase , Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina , Deficiência de alfa 1-Antitripsina/patologia , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/metabolismo , Humanos , Lisossomos/metabolismo , alfa 1-Antitripsina/metabolismo , alfa 1-Antitripsina/genética , Retículo Endoplasmático/metabolismo , Sistemas CRISPR-Cas , Autofagia/genética , Edição de Genes
14.
Phytother Res ; 38(3): 1623-1650, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38302697

RESUMO

Hepatocellular carcinoma (HCC), presently the second leading cause of global cancer-related mortality, continues to pose significant challenges in the realm of medical oncology, impacting both clinical drug selection and mechanistic research. Recent investigations have unveiled autophagy-related signaling as a promising avenue for HCC treatment. A growing body of research has highlighted the pivotal role of autophagy-modulating natural products in inhibiting HCC progression. In this context, we provide a concise overview of the fundamental autophagy mechanism and delineate the involvement of autophagic signaling pathways in HCC development. Additionally, we review pertinent studies demonstrating how natural products regulate autophagy to mitigate HCC. Our findings indicate that natural products exhibit cytotoxic effects through the induction of excessive autophagy, simultaneously impeding HCC cell proliferation by autophagy inhibition, thereby depriving HCC cells of essential energy. These effects have been associated with various signaling pathways, including PI3K/AKT, MAPK, AMPK, Wnt/ß-catenin, Beclin-1, and ferroautophagy. These results underscore the considerable therapeutic potential of natural products in HCC treatment. However, it is important to note that the present study did not establish definitive thresholds for autophagy induction or inhibition by natural products. Further research in this domain is imperative to gain comprehensive insights into the dual role of autophagy, equipping us with a better understanding of this double-edged sword in HCC management.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Macroautofagia , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Autofagia , Proliferação de Células
15.
Nat Cell Biol ; 26(3): 366-377, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38316984

RESUMO

Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain. Notably, core AKC components Atg13 and Atg17 are dispensable for phosphate starvation-induced autophagy revealing significant compositional and functional plasticity of the AKC. Our data indicate that, instead of functioning as a selective autophagy receptor, Pho81 compensates for partially inactive Atg13 by promoting Atg11 phosphorylation by Atg1 critical for pexophagy during phosphate starvation. Our work shows Atg11/FIP200 adaptor subunits bind not only selective autophagy receptors but also modulator subunits that convey metabolic information directly to the AKC for autophagy regulation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Macroautofagia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Transporte/metabolismo , Autofagia/fisiologia , Fagossomos/metabolismo , Fatores de Transcrição/metabolismo , Fosfatos/metabolismo
16.
Cell Rep ; 43(2): 113760, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38340317

RESUMO

Autophagy is crucial for degrading and recycling cellular components. Fusion between autophagosomes and lysosomes is pivotal, directing autophagic cargo to degradation. This process is driven by STX17-SNAP29-VAMP8 and STX7-SNAP29-YKT6 in mammalian cells. However, the interaction between STX17 and YKT6 and its significance remain to be revealed. In this study, we challenge the notion that STX17 and YKT6 function independently in autophagosome-lysosome fusion. YKT6, through its SNARE domain, forms a complex with STX17 and SNAP29 on autophagosomes, enhancing autophagy flux. VAMP8 displaces YKT6 from this complex, leading to the formation of the fusogenic complex STX17-SNAP29-VAMP8. We demonstrated that the YKT6-SNAP29-STX17 complex facilitates both lipid and content mixing driven by STX17-SNAP29-VAMP8, suggesting a priming role of YKT6 for efficient membrane fusion. Our results provide a potential regulation mechanism of autophagosome-lysosome fusion, highlighting the importance of YKT6 and its interactions with STX17 and SNAP29 in promoting autophagy flux.


Assuntos
Autofagossomos , Fusão de Membrana , Animais , Humanos , Macroautofagia , Autofagia , Lisossomos , Mamíferos , Proteínas Qb-SNARE , Proteínas Qc-SNARE , Proteínas R-SNARE , Proteínas Qa-SNARE
17.
Nat Commun ; 15(1): 375, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195640

RESUMO

Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components. Over a dozen selective autophagy pathways mediate the degradation of diverse cellular substrates, but whether these pathways can influence one another remains unknown. We address this question using pexophagy, the autophagic degradation of peroxisomes, as a model. We show in cells that upregulated pexophagy impairs the selective autophagy of both mitochondria and protein aggregates by exhausting the autophagy initiation factor, ULK1. We confirm this finding in cell models of the pexophagy-mediated form of Zellweger Spectrum Disorder, a disease characterized by peroxisome dysfunction. Further, we extend the generalizability of limited selective autophagy by determining that increased protein aggregate degradation reciprocally reduces pexophagy using cell models of Parkinson's Disease and Huntington's Disease. Our findings suggest that the degradative capacity of selective autophagy can become limited by an increase in one substrate.


Assuntos
Doença de Huntington , Doença de Parkinson , Humanos , Macroautofagia/genética , Autofagia/genética , Doença de Huntington/genética , Mitocôndrias/genética , Doença de Parkinson/genética
18.
Autophagy ; 20(5): 1197-1198, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38163952

RESUMO

Under stress conditions, the endoplasmic reticulum and nucleus undergo turnover through selective macroautophagy/autophagy processes termed reticulophagy and nucleophagy, respectively. Our recent study has identified the protein Hva22/Rop1/Yep1, a member of the REEP1-REEP4 subfamily of the REEP protein family, as an essential factor for both processes in the fission yeast Schizosaccharomyces pombe. In the absence of Hva22/Yep1, reticulophagy and nucleophagy cargos without surrounding autophagic membranes accumulate in the cytoplasm. Interestingly, human proteins in the REEP1-REEP4 subfamily can functionally substitute for Hva22/Yep1 to facilitate reticulophagy. Phylogenetic and synteny analyses further reveal that the budding yeast reticulophagy receptor Atg40 is also a REEP1-REEP4 subfamily member. Similar to human REEP1-REEP4 subfamily proteins, Atg40 can functionally replace Hva22/Yep1. Based on our findings, we propose that promoting reticulophagy is a conserved function of REEP1-REEP4 subfamily proteins.


Assuntos
Autofagia , Schizosaccharomyces , Schizosaccharomyces/metabolismo , Humanos , Autofagia/fisiologia , Proteínas de Schizosaccharomyces pombe/metabolismo , Núcleo Celular/metabolismo , Retículo Endoplasmático/metabolismo , Macroautofagia/fisiologia
19.
Autophagy ; 20(5): 1208-1209, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38293799

RESUMO

Selective degradation of the endoplasmic reticulum (ER) by macroautophagy/autophagy (reticulophagy) is essential for maintaining ER morphology and homeostasis under environmental stresses. Several reticulophagy receptors have been identified in mammals and yeast, but their counterparts in plants have not been extensively explored yet. Recently, we demonstrated that the HVA22-family protein OsHLP1 is a reticulophagy receptor in rice plants, and its orthologs function similarly in Arabidopsis plants. In this punctum, we discuss why the HVA22 family proteins are the reticulophagy receptors in plants and how reticulophagy is highly associated with plant immune response.


Assuntos
Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Autofagia/fisiologia , Proteínas de Plantas/metabolismo , Macroautofagia/fisiologia , Arabidopsis/metabolismo , Arabidopsis/genética , Plantas/metabolismo , Animais
20.
Cells ; 13(1)2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38201307

RESUMO

Autophagy is a major degradative pathway that plays a key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed in a double-membrane autophagosome that fuses with lysosomes, is orchestrated by a complex cascade of events. Autophagy has a particularly strong impact on the nervous system, and mutations in core components cause numerous neurological diseases. We first review the regulation of autophagy, from autophagosome biogenesis to lysosomal degradation and associated neurodevelopmental/neurodegenerative disorders. We then describe how this process is specifically regulated in the axon and in the somatodendritic compartment and how it is altered in diseases. In particular, we present the neuronal specificities of autophagy, with the spatial control of autophagosome biogenesis, the close relationship of maturation with axonal transport, and the regulation by synaptic activity. Finally, we discuss the physiological functions of autophagy in the nervous system, during development and in adulthood.


Assuntos
Autofagia , Macroautofagia , Autofagossomos , Transporte Axonal , Lisossomos
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