ATG16L1 functions in cell homeostasis beyond autophagy

Hamaoui, Daniel; Subtil, Agathe

doi:10.1111/febs.15833

Cited by 24 publications

(17 citation statements)

References 127 publications

(176 reference statements)

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“…The binding of Beclin-1 to autophagy precursors results in the initiation of autophagosome formation [ 55 ]. The triplet complex that is formed by the sequential conjugation of Atg12, Atg5, and Atg16L is indispensable for autophagosome formation [ 56 ]. Our results show that the levels of Beclin-1 were elevated in SHSY-5Y cells exposed to PS-NPs compared to the control ( Figure 3 A,B).…”

Section: Resultsmentioning

confidence: 99%

PS-NPs Induced Neurotoxic Effects in SHSY-5Y Cells via Autophagy Activation and Mitochondrial Dysfunction

Tang

Chen

et al. 2022

Brain Sciences

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Polystyrene nanoparticles (PS-NPs) are organic pollutants that are widely detected in the environment and organisms, posing potential threats to both ecosystems and human health. PS-NPs have been proven to penetrate the blood–brain barrier and increase the incidence of neurodegenerative diseases. However, information relating to the pathogenic molecular mechanism is still unclear. This study investigated the neurotoxicity and regulatory mechanisms of PS-NPs in human neuroblastoma SHSY-5Y cells. The results show that PS-NPs caused obvious mitochondrial damages, as evidenced by inhibited cell proliferation, increased lactate dehydrogenase release, stimulated oxidative stress responses, elevated Ca2+ level and apoptosis, and reduced mitochondrial membrane potential and adenosine triphosphate levels. The increased release of cytochrome c and the overexpression of apoptosis-related proteins apoptotic protease activating factor-1 (Apaf-1), cysteinyl aspartate specific proteinase-3 (caspase-3), and caspase-9 indicate the activation of the mitochondrial apoptosis pathway. In addition, the upregulation of autophagy markers light chain 3-II (LC3-II), Beclin-1, and autophagy-related protein (Atg) 5/12/16L suggests that PS-NPs could promote autophagy in SHSY-5Y cells. The RNA interference of Beclin-1 confirms the regulatory role of autophagy in PS-NP-induced neurotoxicity. The administration of antioxidant N-acetylcysteine (NAC) significantly attenuated the cytotoxicity and autophagy activation induced by PS-NP exposure. Generally, PS-NPs could induce neurotoxicity in SHSY-5Y cells via autophagy activation and mitochondria dysfunction, which was modulated by mitochondrial oxidative stress. Mitochondrial damages caused by oxidative stress could potentially be involved in the pathological mechanisms for PS-NP-induced neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

PS-NPs Induced Neurotoxic Effects in SHSY-5Y Cells via Autophagy Activation and Mitochondrial Dysfunction

Tang

Chen

et al. 2022

Brain Sciences

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“…However, in ATG16L1-de cient cells, autophagosome formation and protein degradation are seriously affected [30]. Many studies used the ATG16L1 silencing gene to block the binding of the ATG12-ATG5 complex with cell membranes, causing autophagy to weaken and hindering the formation of autophagosomes [31]. Therefore, ATG5 and ATG16L1 can be used as detection indexes in the autophagosome formation stage.…”

Section: Discussionmentioning

confidence: 99%

Regulatory Effects of Survivin on Autolysosome Formation-Related Proteins in Esophageal Carcinoma Cells

LIU

Aiziti

et al. 2022

Preprint

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Purpose:To investigate the regulatory effect of Survivin on autolysosome formation-associated proteins in esophageal cancer cell (ESCC) line Eca109.Methods: An autophagy induction model was constructed using rapamycin (RAPA), an autophagy inhibitor. The Survivin overexpression vector, shRNA vector, and Survivin inhibitor YM155 were used to interfere with the autophagy model. Laser copolymer microscopy technology was utilized to observe the changes in autophagosomes and their progression, while western blotting was used to detect the the level of lysosome formation-related proteins after autophagy. Besides, immunofluorescence staining was used to determine the pH of lysosomes and the distribution of cathepsin-D in cells.Results: (1)Eca109 cells transfected with MRFP-EGFP-LC3 vector by RAPA showed a significant increase in green fluorescence, indicating an increase in autophagosomes. Results from western blotting indicated a rise in protein expression levels of LC3-I and LC3-II, an increase in the ratio of LC3-II/LC3-I, and a decrease in the expression of p62 levels, indicating enhanced autophagy. (2)In the autophagy model of Eca109 cells, after Survivin overexpression, LC3 expression increased, ATG5 expression decreased(P<0.05). After YM155 intervention, ATG5 and ATG16L1 expression rose(P<0.05). (3)In the autophagy model of Eca109 cells, Rab7 and ATG5 expression increased,while ATG16L1 expression decreased(P<0.05) after YM155 intervention and Survivin shRNA transfection. In the presence of the Survivin overexpression vector, YM155 interfered with the expression of ATG5, ATG16L1, and Rab7 in the autophagy model(P<0.05).(4)Decreased Survivin can reduce p62 expression and increase autophagy.(5)Survivin overexpression increased the number of intracellular lysosomes and was involved in the regulation of lysosomal pH changes. Besides, inhibition of Survivin expression resulted in the extravasation of cathepsin-D, which was dispersive and affected the permeability of lysosomes.Conclusion: Survivin expression was directly related to the expression of the autophagy-associated protein LC3 and P62.Survivin is associated with the autophagic process in cancer cells at specific periods, which indicates that Survivin is involved in both early autophagy formation and the later stages of autolysosomal function implementation.

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“…ATG16L1 has been shown to attenuate proinflammatory cytokine responses in innate immunity (Table 1 )[ 8 ]. RLRs, including RIG-I and melanoma differentiation-associated gene 5 (MDA5), are sensors for RNA viruses[ 3 ].…”

Section: Atg16l1 and Innate Immunitymentioning

confidence: 99%

“…In addition to its role in autophagy, ATG16L1 has been shown to be involved in PRR-mediated innate immunity. ATG16L1 negatively regulates pro-inflammatory and type I interferon (IFN-I) responses mediated by TLRs, NLRs, and RLRs[ 8 ]. More importantly, the loss-of-function mutation T300A in ATG16L1 has been identified as a risk factor for CD in parallel with mutations in NOD2 [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Alterations of autophagic and innate immune responses by the Crohn’s disease-associated ATG16L1 mutation

Okai¹,

Watanabe²,

Minaga³

et al. 2022

WJG

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Crohn’s disease (CD) is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines. These pro-inflammatory cytokines are produced by macrophages and dendritic cells (DCs) upon sensing the intestinal microbiota by the pattern recognition receptors (PRRs). Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation, as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development. Autophagy is an intracellular degradation process, during which cytoplasmic nutrients and intracellular pathogens are digested. Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs, it is likely that dysfunction of the autophagic machinery is involved in the development of CD. Indeed, the loss-of-function mutation T300A in the autophagy related 16 like 1 (ATG16L1) protein, a critical regulator of autophagy, increases susceptibility to CD. Recent studies have provided evidence that ATG16L1 is involved not only in autophagy, but also in PRR-mediated signaling pathways. ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs. Here, we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.

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ATG16L1 functions in cell homeostasis beyond autophagy

Cited by 24 publications

References 127 publications

PS-NPs Induced Neurotoxic Effects in SHSY-5Y Cells via Autophagy Activation and Mitochondrial Dysfunction

PS-NPs Induced Neurotoxic Effects in SHSY-5Y Cells via Autophagy Activation and Mitochondrial Dysfunction

Regulatory Effects of Survivin on Autolysosome Formation-Related Proteins in Esophageal Carcinoma Cells

Alterations of autophagic and innate immune responses by the Crohn’s disease-associated ATG16L1 mutation

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