RESUMO
The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy.
Assuntos
Autofagossomos/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Western Blotting , Imunofluorescência , Células HEK293 , Células HeLa , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/genética , Proteínas/genética , Interferência de RNARESUMO
Autophagy allows the degradation of cytosolic endogenous and exogenous material in the lysosome. Substrates are engulfed by double-membrane vesicles, coined autophagosomes, which subsequently fuse with lysosomes. Depending on the involvement of specific receptor proteins, autophagy occurs in a selective or nonselective manner. While this process is well understood at the level of bulky cargo such as mitochondria and bacteria, we know very little about individual proteins and protein complexes that are engulfed and degraded by autophagy. In contrast to the critical role of autophagy in balancing proteostasis, our current knowledge of the autophagic degradome is very limited. Here, we combined proximity labeling with quantitative proteomics to systematically map the protein inventory of autophagosomes. Using this strategy, we uncovered a basal, housekeeping mitophagy pathway that involves piecemeal degradation of mitochondrial proteins in a LC3C- and p62-dependent manner and contributes to mitochondrial homeostasis maintenance when cells rely on oxidative phosphorylation.
Assuntos
Proteínas Associadas aos Microtúbulos/metabolismo , Mitofagia/fisiologia , Fosforilação Oxidativa , Fagossomos/metabolismo , Proteólise , Células HeLa , Humanos , Proteínas Associadas aos Microtúbulos/genética , Fagossomos/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
Microtubule-associated protein 1 light chain 3 gamma (MAP1LC3C or LC3C) is a member of the microtubule-associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor-suppressing activity, and its expression is dependent on kidney cancer tumor suppressors, such as von Hippel-Lindau protein and folliculin. Recently, we demonstrated that LC3C autophagy is regulated by noncanonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cell stemness. Here, we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE). This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of zinc (Zn)-related genes and activity of polycomb repressor complex 2, accompanied by a robust decrease in intracellular Zn. In addition, metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show increased tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of lysosomal-associated membrane protein 1 on the plasma membrane of cancer cells in human clear cell renal cell carcinoma and reduced levels of Zn, suggesting that LE occurs in clear cell renal cell carcinoma, potentially contributing to the loss of Zn. These data indicate that the reprogramming of lysosomal localization and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor-propagating cancer cells is an important aspect of tumor-suppressing activity of LC3C.
Assuntos
Carcinoma de Células Renais , Exocitose , Neoplasias Renais , Lisossomos , Proteínas Associadas aos Microtúbulos , Zinco , Animais , Humanos , Autofagia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Lisossomos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Zinco/metabolismo , Complexo Repressor Polycomb 2 , Epigênese GenéticaRESUMO
PURPOSE: Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer characteristic of high recurrence rate and poor prognosis. According to previous studies and bioinformatics prediction, PGM5P3-AS1 has been found to be significantly down-regulated in TNBC cells. In addition, cell ferroptosis has become a hotspot in breast cancer research and TNBC has been reported to be more sensitive to ferroptosis than receptor positive breast cancer. Hence, we aim at exploring the molecular mechanism of PGM5P3-AS1 in TNBC cells and further explore whether PGM5P3-AS1 can inhibit TNBC progression via promoting cell ferroptosis. METHODS: The expression of genes in TNBC cells was verified by RT-qPCR assay. Functional assays were taken to evaluate the impact PGM5P3-AS1 may exert on TNBC progression. The regulatory pattern of PGM5P3-AS1 on cell ferroptosis in TNBC was validated through mechanism assays. RESULTS: PGM5P3-AS1 was proved to be down-regulated in TNBC cells and suppressed TNBC cell proliferation as well as migration. PGM5P3-AS1 promoted cell ferroptosis in TNBC by recruiting RNA-binding protein (RBP) NOP58 to stabilize MAP1LC3C mRNA, and thus inhibiting TNBC progression. CONCLUSION: PGM5P3-AS1 regulated MAP1LC3C to promote cell ferroptosis and thus inhibiting the malignant progression of TNBC.
Assuntos
Ferroptose , Proteínas Associadas aos Microtúbulos , RNA Antissenso , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Associadas aos Microtúbulos/genética , RNA Antissenso/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Autophagy is a catabolic process in which a double-membrane organelle, the autophagosome (AP), engulfs cellular components that will be degraded in the lysosomes. ATG8 protein family members participate at various stages of AP formation. The present study compares the capacity to induce lipid-vesicle tethering and fusion of two ATG8 family members, LC3B and LC3C, with model membranes. LC3B is the most thoroughly studied ATG8 protein. It is generally considered as an autophagosomal marker and a canonical representative of the LC3 subfamily. LC3C is less studied, but recent data have reported its implication in various processes, crucial to cellular homeostasis. The results in this paper show that LC3C induces higher levels of tethering and of intervesicular lipid mixing than LC3B. As the N-terminus of LC3C is different from that of the other family members, various mutants of the N-terminal region of both LC3B and LC3C were designed, and their activities compared. It was concluded that the N-terminal region of LC3C was responsible for the enhanced vesicle tethering, membrane perturbation and vesicle-vesicle fusion activities of LC3C as compared to LC3B. The results suggest a specialized function of LC3C in the AP expansion process.
Assuntos
Fusão de Membrana , Proteínas Associadas aos Microtúbulos , Família da Proteína 8 Relacionada à Autofagia/genética , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Autofagia , LipídeosRESUMO
Among the MAP1LC3/LC3 subfamily of Atg8 proteins, LC3B and LC3C constitute the most and least studied members, respectively, LC3B being generally considered as an autophagosomal marker and a canonical representative of the LC3 subfamily. In several recent studies, LC3C has emerged as an important modulator in various processes of cell homeostasis. Our own research data demonstrate that LC3C induces higher levels of tethering and of intervesicular lipid mixing than LC3B. LC3C contains a peculiar N-terminal region, different from the other Atg8-family protein members. Using a series of mutants, we have shown that the N-terminal region of LC3C is responsible for the enhanced vesicle tethering, membrane perturbation and vesicle-vesicle fusion activities of LC3C as compared to LC3B.Abbreviations: ATG: autophagy related; GABARAP: gamma-aminobutyric acid receptor associated protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PC: phosphatidyl choline; PE: phosphatidylethanolamine; PEmal: maleimide-derivatized PE; PtdIns: phosphatidylinositol.
RESUMO
Macroautophagy/autophagy acts to promote homeostasis and is increasingly understood to selectively target cargo for degradation. The LC3-family of proteins mediate diverse yet distinct cargo recruitment to phagophores. However, what underlies specificity for cargo engagement among LC3 proteins is poorly understood. Using an unbiased protein interaction screen of LC3B and LC3C, we uncover a novel LC3C-endocytic-associated-pathway (LEAP) that recruits selective plasma membrane (PM) cargo to phagophores. We show LC3C but not LC3B localizes to peripheral endosomes and engages proteins that traffic between the PM, endosomes and autophagosomes. We establish that endocytic LC3C binds cargo internalized from the PM, including MET receptor tyrosine kinase and TFRC (transferrin receptor), and targets them toward autophagic degradation. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signaling and autophagic degradation with important implications in cancer and other disease states.
Assuntos
Autofagia , Proteínas Associadas aos Microtúbulos , Proteínas Associadas aos Microtúbulos/metabolismo , Autofagossomos/metabolismo , Transdução de Sinais , MacroautofagiaRESUMO
Understanding how viruses evade innate defenses to efficiently spread in their hosts is crucial in the fight against infections. In our study, we provided new insights on the first step initiating an LC3C (microtubule associated protein 1 light chain 3 gamma)-associated degradative pathway exploited by HIV-1 (human immunodeficiency virus type 1) to overcome the antiviral action of the restriction factor BST2 (bone marrow stromal cell antigen 2)/tetherin. We have uncovered an unsuspected and unconventional function of the autophagy-related protein ATG5 in the recognition and engagement of BST2 molecules trapping viruses at the plasma membrane, and directing them toward this LC3C-associated pathway for degradation. Additionally, we highlighted that HIV-1 uses this LC3C-associated process to attenuate the inflammatory responses triggered by BST2-mediated sensing of viruses.
RESUMO
Endoplasmic reticulum (ER)-phagy is crucial to regulate the function and homeostasis of the ER via lysosomal degradation, but how it is initiated is unclear. Here we discover that Z-AAT, a disease-causing mutant of α1-antitrypsin, induces noncanonical ER-phagy at ER exit sites (ERESs). Accumulation of misfolded Z-AAT at the ERESs impairs coat protein complex II (COPII)-mediated ER-to-Golgi transport and retains V0 subunits that further assemble V-ATPase at the arrested ERESs. V-ATPase subsequently recruits ATG16L1 onto ERESs to mediate in situ lipidation of LC3C. FAM134B-II is then recruited by LC3C via its LIR motif and elicits ER-phagy leading to efficient lysosomal degradation of Z-AAT. Activation of this ER-phagy mediated by the V-ATPase-ATG16L1-LC3C axis (EVAC) is also triggered by blocking ER export. Our findings identify a pathway which switches COPII-mediated transport to lysosomal degradation for ER quality control.
Assuntos
Adenosina Trifosfatases , Lisossomos , Adenosina Trifosfatases/metabolismo , Lisossomos/metabolismo , Transporte Proteico/fisiologia , Complexo de Golgi/metabolismo , Retículo Endoplasmático/metabolismo , AutofagiaRESUMO
Macroautophagy is a conserved degradative process for maintaining cellular homeostasis and plays a key role in aging and various human disorders. The microtubule-associated protein 1A/1B light chain 3B (MAP1LC3B or LC3B) is commonly analyzed as a key marker for autophagosomes and as a proxy for autophagic flux. Three paralogues of the LC3 gene exist in humans: LC3A, LC3B and LC3C. The molecular function, regulation and cellular localization of LC3A and LC3C have not been investigated frequently, even if a similar function to that described for LC3B appears likely. Here, we have selectively decapacitated LC3B by three separate strategies in primary human fibroblasts and analyzed the evoked effects on LC3A, LC3B and LC3C in terms of their cellular distribution and co-localization with p62, a ubiquitin and autophagy receptor. First, treatment with pharmacological sirtuin 1 (SIRT1) inhibitors to prevent the translocation of LC3B from the nucleus into the cytosol induced an increase in cytosolic LC3C, a heightened co-localization of LC3C with p62, and an increase LC3C-dependent autophagic flux as assessed by protein lipidation. Cytosolic LC3A, however, was moderately reduced, but also more co-localized with p62. Second, siRNA-based knock-down of SIRT1 broadly reproduced these findings and increased the co-localization of LC3A and particularly LC3C with p62 in presumed autophagosomes. These effects resembled the effects of pharmacological sirtuin inhibition under normal and starvation conditions. Third, siRNA-based knock-down of total LC3B in cytosol and nucleus also induced a redistribution of LC3C as if to replace LC3B in the nucleus, but only moderately affected LC3A. Total protein expression of LC3A, LC3B, LC3C, GABARAP and GABARAP-L1 following LC3B decapacitation was unaltered. Our data indicate that nuclear trapping and other causes of LC3B functional loss in the cytosol are buffered by LC3A and actively compensated by LC3C, but not by GABARAPs. The biological relevance of the potential functional compensation of LC3B decapacitation by LC3C and LC3A warrants further study.
Assuntos
Autofagossomos/metabolismo , Fibroblastos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Sequência de Aminoácidos , Especificidade de Anticorpos/imunologia , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Sítios de Ligação , Linhagem Celular , Núcleo Celular/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Lipídeos/química , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Filogenia , Transporte Proteico , RNA Interferente Pequeno/metabolismo , Sirtuínas/metabolismo , Frações Subcelulares/metabolismoRESUMO
Macroautophagy/autophagy is an evolutionarily conserved degradative process with a central role in maintaining cellular homeostasis under conditions of stress, and recent evidence suggests this may occur in part through direct modification of cell signaling. The MET/HGF receptor tyrosine kinase (RTK) signaling axis is an important mediator of cell motility and invasion in normal cell functions and in cancer. We discovered a role for autophagy in regulating ligand-activated MET signaling and cellular responses. When autophagy is induced by starvation, the HGF-activated and internalized MET RTK is selectively recruited for autophagic degradation through complex formation with the MAP1LC3C autophagy protein. Decreased LC3C expression in cancer results in loss of autophagic degradation of MET and enhanced HGF-stimulated cell invasion implicated in metastatic progression. This emerging role for autophagy in selectively regulating signaling proteins has implications for understanding cellular adaptations to stress and the functions of autophagy at different stages of cancer progression.
Assuntos
Autofagia/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Macroautofagia/fisiologia , Transdução de Sinais/fisiologiaRESUMO
The Met/hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) is deregulated in many cancers and is a recognized target for cancer therapies. Following HGF stimulation, the signaling output of Met is tightly controlled by receptor internalization and sorting for degradation or recycling. Here, we uncover a role for autophagy in selective degradation of Met and regulation of Met-dependent cell migration and invasion. Met engagement with the autophagic pathway is dependent on complex formation with the mammalian ATG8 family member MAP1LC3C. LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, allowing identification of LC3C domains required for rescue. Cancer cells with low LC3C levels show enhanced Met stability, signaling, and cell invasion. These findings provide mechanistic insight into RTK recruitment to autophagosomes and establish distinct roles for ATG8 proteins in this process, supporting that differential expression of ATG8 proteins can shape the functional consequences of autophagy in cancer development and progression.
Assuntos
Autofagia/fisiologia , Movimento Celular/efeitos dos fármacos , Fator de Crescimento de Hepatócito/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Autofagia/genética , Linhagem Celular Tumoral , Imunofluorescência , Humanos , Proteínas Associadas aos Microtúbulos/genética , Modelos Biológicos , Transporte Proteico/genética , Transporte Proteico/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Autophagy is a versatile catabolic pathway for lysosomal degradation of cytoplasmic material. While the phenomenological and molecular characteristics of autophagic non-selective (bulk) decomposition have been investigated for decades, the focus of interest is increasingly shifting towards the selective mechanisms of autophagy. Both, selective as well as bulk autophagy critically depend on ubiquitin-like modifiers belonging to the Atg8 (autophagy-related 8) protein family. During evolution, Atg8 has diversified into eight different human genes. While all human homologues participate in the formation of autophagosomal membrane compartments, microtubule-associated protein light chain 3C (LC3C) additionally plays a unique role in selective autophagic clearance of intracellular pathogens (xenophagy), which relies on specific protein-protein recognition events mediated by conserved motifs. The sequence-specific (1)H, (15)N, and (13)C resonance assignments presented here form the stepping stone to investigate the high-resolution structure and dynamics of LC3C and to delineate LC3C's complex network of molecular interactions with the autophagic machinery by NMR spectroscopy.
Assuntos
Autofagia , Proteínas Associadas aos Microtúbulos/química , Ressonância Magnética Nuclear Biomolecular , Sequência de Aminoácidos , Isótopos de Carbono , Humanos , Isótopos de Nitrogênio , TrítioRESUMO
BST2 (bone marrow stromal antigen 2)/tetherin is a restriction factor of enveloped viruses, which blocks the release of viral particles. HIV-1 encodes proteins that antagonize this innate barrier, including the accessory protein Vpu. Here, we investigate whether the autophagy pathway and/or ATG proteins are hijacked by HIV-1 Vpu to circumvent BST2 restriction of viral release. We report that BST2 and Vpu are present in LC3-positive compartments. We found that Vpu selectively interacts with the ATG8 ortholog LC3C through the Vpu L63VEM66 sequence. This sequence is required for Vpu to antagonize BST2 restriction. LC3C expression favors the removal of BST2 from the HIV-1 budding site, and thus HIV-1 release in BST2-expressing cells. Additionally, ATG5 and beclin 1/ATG6, but not all the components of the autophagy pathway, act with LC3C to facilitate Vpu antagonism of BST2 restriction. Altogether, our data support the view that a non-canonical autophagy pathway reminiscent of LC3-associated phagocytosis contributes to Vpu counteraction of BST2 restriction.
Assuntos
Antígenos CD/metabolismo , Autofagia , HIV-1/metabolismo , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Liberação de Vírus , Sequência de Aminoácidos , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Ligadas por GPI/metabolismo , Células HEK293 , Células HeLa , Proteínas do Vírus da Imunodeficiência Humana/química , Humanos , Ligação Proteica , Proteínas Virais Reguladoras e Acessórias/químicaRESUMO
Autophagy defends the mammalian cytosol against bacterial invasion. Efficient bacterial engulfment by autophagy requires cargo receptors that bind (a) homolog(s) of the ubiquitin-like protein Atg8 on the phagophore membrane. The existence of multiple ATG8 orthologs in higher eukaryotes suggests that they may perform distinct functions. However, no specific role has been assigned to any mammalian ATG8 ortholog. We recently discovered that the autophagy receptor CALCOCO2/NDP52, which detects cytosol-invading Salmonella enterica serovar Typhimurium (S. Typhimurium), preferentially binds LC3C. The CALCOCO2/NDP52-LC3C interaction is essential for cell-autonomous immunity against cytosol-exposed S. Typhimurium, because cells lacking either protein fail to target bacteria into the autophagy pathway. The selectivity of CALCOCO2/NDP52 for LC3C is determined by a novel LC3C interacting region (CLIR), in which the lack of the key aromatic residue of canonical LIRs is compensated by LC3C-specific interactions. Our findings provide a new layer of regulation to selective autophagy, suggesting that specific interactions between autophagy receptors and the ATG8 orthologs are of biological importance.
Assuntos
Autofagia , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Salmonella typhimurium/metabolismo , Homologia de Sequência de Aminoácidos , Proteínas de Transporte/metabolismo , Humanos , Modelos Biológicos , Ligação Proteica , Salmonella typhimurium/crescimento & desenvolvimentoRESUMO
Autophagy is a highly conserved cellular response to starvation that leads to the degradation of organelles and long-lived proteins in lysosomes and is important for cellular homeostasis, tissue development and as a defense against aggregated proteins, damaged organelles and infectious agents. Although autophagy has been studied in many animal species, reagents to study autophagy in avian systems are lacking. Microtubule-associated protein 1 light chain 3 (MAP1LC3/LC3) is an important marker for autophagy and is used to follow autophagosome formation. Here we report the cloning of avian LC3 paralogs A, B and C from the domestic chicken, Gallus gallus domesticus, and the production of replication-deficient, recombinant adenovirus vectors expressing these avian LC3s tagged with EGFP and FLAG-mCherry. An additional recombinant adenovirus expressing EGFP-tagged LC3B containing a G120A mutation was also generated. These vectors can be used as tools to visualize autophagosome formation and fusion with endosomes/lysosomes in avian cells and provide a valuable resource for studying autophagy in avian cells. We have used them to study autophagy during replication of infectious bronchitis virus (IBV). IBV induced autophagic signaling in mammalian Vero cells but not primary avian chick kidney cells or the avian DF1 cell line. Furthermore, induction or inhibition of autophagy did not affect IBV replication, suggesting that classical autophagy may not be important for virus replication. However, expression of IBV nonstructural protein 6 alone did induce autophagic signaling in avian cells, as seen previously in mammalian cells. This may suggest that IBV can inhibit or control autophagy in avian cells, although IBV did not appear to inhibit autophagy induced by starvation or rapamycin treatment.
Assuntos
Autofagia , Galinhas/virologia , Vírus da Bronquite Infecciosa/fisiologia , Transdução de Sinais , Sequência de Aminoácidos , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Vírus da Bronquite Infecciosa/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Fusão de Membrana/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/química , Dados de Sequência Molecular , Fagossomos/efeitos dos fármacos , Fagossomos/metabolismo , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Autophagy is an important mechanism in cancer cell survival and tumor growth and plays both pro- and anti-oncogenic roles. However, the biochemical basis for these diverse functions is not well understood. Our work provides new evidence for the existence of two separate autophagic programs regulated in an opposite manner by the von Hippel-Lindau tumor suppressor (VHL). These programs, marked by differential requirements for LC3B vs. LC3C, play tumor-promoting and tumor-suppressing roles in renal cancer.