Lens autophagy protein ATG16L1: a potential target for cataract treatment
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ABSTRACT:
SUBMITTER: Cui Y
PROVIDER: S-EPMC11234268 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundHsf4 is closely related to the development of cataract. However, the molecular mechanisms remain unknown. This study aimed to explore the molecular mechanisms that how Hsf4 mutations influence development of lens and thus lead to cataract in mouse.MethodsThe mRNA expression profile of mouse tissue samples from Hsf4-null and wile-type lenses was downloaded from Gene Expression Omnibus database. Then the LIMMA package was used to screen differentially expressed genes (DEGs) and DAVID was applied to identify the significantly enriched Gene Ontology (GO) categories for DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed using Cytoscape and the key modules were selected from the PPI network based on the MCODE analysis.ResultsA total of 216 DEGs were screened, including 51 up- and 165 down-regulated genes. Meanwhile, nine GO terms were obtained, and DEGs such as SGK1, CRY2 and REV1 were enriched in response to DNA damage stimulus. Furthermore, 89 DEGs and 99 gene pairs were mapped into the PPI network and Ubc was the hob node. Two key modules, which contained the genes (e.g. Ubc, Egr1, Ptgs2, Hmox1, Cd44, Btg2, Cyr61 and Fos) were related to response to DNA damage stimulus.ConclusionsThe deletion of Hsf4 affects the expression of many genes, such as Ubc, Ptgs2, Egr1 and Fos. These genes may be involved in the development of cataract and could be used as therapeutic targets for cataract.
| S-EPMC4506420 | biostudies-literature
Project description:A variant of the autophagy gene ATG16L1 is associated with Crohn's disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis. This cytoprotective function of ATG16L1 was associated with the role of autophagy in promoting mitochondrial homeostasis. Finally, therapeutic blockade of necroptosis through TNFα or RIPK1 inhibition ameliorated disease in the virally triggered IBD model. These findings indicate that, in contrast to tumor cells in which autophagy promotes caspase-independent cell death, ATG16L1 maintains the intestinal barrier by inhibiting necroptosis in the epithelium.
| S-EPMC5716041 | biostudies-literature
Project description:Previously we reported that adipocyte SNAP23 (synaptosome-associated protein of 23 kDa) deficiency blocks the activation of macroautophagy, leading to an increased abundance of BAX, a pro-death Bcl-2 family member, and activation and adipocyte cell death both in vitro and in vivo Here, we found that knockdown of SNAP23 inhibited the association of the autophagosome regulators ATG16L1 and ATG9 compartments by nutrient depletion and reduced the formation of ATG16L1 membrane puncta. ATG16L1 knockdown inhibited autophagy flux and increased BAX protein levels by suppressing BAX degradation. The elevation in BAX protein had no effect on BAX activation or cell death in the nutrient-replete state. However, following nutrient depletion, BAX was activated with a concomitant induction of cell death. Co-immunoprecipitation analyses demonstrated that SNAP23 and ATG16L1 proteins form a stable complex independent of nutrient condition, whereas in the nutrient-depleted state, BAX binds to SNAP23 to form a ternary BAX-SNAP23-ATG16L1 protein complex. Taken together, these data support a model in which SNAP23 plays a crucial function as a scaffold for ATG16L1 necessary for the suppression of BAX activation and induction of the intrinsic cell death program.
| S-EPMC7606669 | biostudies-literature
Project description:PurposeTo describe the differences in treatment costs for infants randomized to contact lens correction versus primary intraocular lens (IOL) implantation after unilateral cataract surgery in the Infant Aphakia Treatment Study (IATS).DesignRetrospective cost analysis of a prospective, randomized clinical trial based on Georgia Medicaid data and the actual costs of supplies used.ParticipantsThe IATS is a randomized, multicenter (n=12) clinical trial comparing treatment of aphakia with a primary IOL or contact lens in 114 infants with unilateral congenital cataract.InterventionInfants underwent cataract surgery with or without placement of an IOL.Main outcome measuresThe mean cost of cataract surgery and all additional surgeries, examinations, and supplies used up to 12 months of age.ResultsThe mean cost of treatment for a unilateral congenital cataract with primary IOL implantation was $14 752 versus $10 726 with contact lens correction. The initial cataract surgery accounted for approximately 50% of the treatment costs for both groups. Contact lens costs accounted for 15% ($1600/patient) in the aphakic group, whereas glasses costs represented only 4% ($535/patient) in the IOL group. The increased costs in the IOL group were primarily due to the higher cost of cataract surgery in this group ($7302 vs. $5357) and the cost of additional operations.ConclusionsFor IATS patients up to 12 months of age, cataract surgery coupled with IOL implantation and spectacle correction was 37.5% (∼$4000) more expensive than cataract surgery coupled with contact lens correction.Financial disclosure(s)The author(s) have no proprietary or commercial interest in any materials discussed in this article.
| S-EPMC3536935 | biostudies-literature
Project description:PurposeTo analyze differences in the cost of treatment for infants randomized to primary intraocular lens (IOL) implantation versus optical correction with a contact lens (CL) after unilateral cataract surgery in the Infant Aphakia Treatment Study (IATS).DesignRetrospective cost analysis of a prospective, randomized clinical trial based on Georgia Medicaid reimbursement data as well as actual costs of supplies used during the study, adjusted for inflation.ParticipantsThe IATS is a multicenter (n = 12), randomized clinical trial comparing the optical treatment of aphakia with either primary IOL implantation (n = 57) or CL correction (n = 57) in 114 infants with unilateral congenital cataract.InterventionOne hundred fourteen infants underwent unilateral cataract surgery and were either corrected optically by primary IOL implantation at the time of surgery or were corrected with a CL after surgery.Main outcome measuresThe mean cost of cataract surgery and all additional surgeries, examinations, and supplies used up to 5 years of age.ResultsThe 5-year treatment cost of an infant with a unilateral congenital cataract corrected optically with an IOL was $27 090 versus $25 331 for a patient treated with a CL after initial cataract surgery. The total cost of supplies was $3204 in the IOL group versus $7728 in the CL group.ConclusionsUnilateral cataract surgery in infancy coupled with primary IOL implantation is approximately 7% more expensive than aphakia and CL correction. Patient costs are more than double with CL versus IOL treatment.
| S-EPMC4306643 | biostudies-literature
Project description:Host resistance to viral infection requires type I (α/β) and II (γ) interferon (IFN) production. Another important defense mechanism is the degradative activity of macroautophagy (herein autophagy), mediated by the coordinated action of evolutionarily conserved autophagy proteins (Atg). We show that the Atg5-Atg12/Atg16L1 protein complex, whose prior known function is in autophagosome formation, is required for IFNγ-mediated host defense against murine norovirus (MNV) infection. Importantly, the direct antiviral activity of IFNγ against MNV in macrophages required Atg5-Atg12, Atg7, and Atg16L1, but not induction of autophagy, the degradative activity of lysosomal proteases, fusion of autophagosomes and lysosomes, or the Atg8-processing protein Atg4B. IFNγ, via Atg5-Atg12/Atg16L1, inhibited formation of the membranous cytoplasmic MNV replication complex, where Atg16L1 localized. Thus, the Atg5-Atg12/Atg16L1 complex performs a pivotal, nondegradative role in IFNγ-mediated antiviral defense, establishing that multicellular organisms have evolved to use portions of the autophagy pathway machinery in a cassette-like fashion for host defense.
| S-EPMC3348177 | biostudies-literature
Project description:Γ-Crystallins play a major role in age-related lens transparency. Their destabilization by mutations and physical chemical insults are associated with cataract formation. Therefore, drugs that increase their stability should have anticataract properties. To this end, we screened 2560 Federal Drug Agency-approved drugs and natural compounds for their ability to suppress or worsen H2O2 and/or heat-mediated aggregation of bovine γ-crystallins. The top two drugs, closantel (C), an antihelminthic drug, and gambogic acid (G), a xanthonoid, attenuated thermal-induced protein unfolding and aggregation as shown by turbidimetry fluorescence spectroscopy dynamic light scattering and electron microscopy of human or mouse recombinant crystallins. Furthermore, binding studies using fluorescence inhibition and hydrophobic pocket-binding molecule bis-8-anilino-1-naphthalene sulfonic acid revealed static binding of C and G to hydrophobic sites with medium-to-low affinity. Molecular docking to HγD and other γ-crystallins revealed two binding sites, one in the "NC pocket" (residues 50-150) of HγD and one spanning the "NC tail" (residues 56-61 to 168-174 in the C-terminal domain). Multiple binding sites overlap with those of the protective mini αA-crystallin chaperone MAC peptide. Mechanistic studies using bis-8-anilino-1-naphthalene sulfonic acid as a proxy drug showed that it bound to MAC sites, improved Tm of both H2O2 oxidized and native human gamma D, and suppressed turbidity of oxidized HγD, most likely by trapping exposed hydrophobic sites. The extent to which these drugs act as α-crystallin mimetics and reduce cataract progression remains to be demonstrated. This study provides initial insights into binding properties of C and G to γ-crystallins.
| S-EPMC9525908 | biostudies-literature
Project description:We describe in this article an effective and safe modification of hydrodissection technique in cataract surgery. The hydrodissection cannula tip is inserted into the capsulorhexis edge near the primary incision, with the cannula elbow resisting on the upper lip of the primary incision. Hydrodissection is then completed effectively and safely by squirting fluid to cleave the lens and capsular. This modified hydrodissection technique can be performed with high reproducibility and in a short practice period.
| S-EPMC10230007 | biostudies-literature
Project description:BackgroundPaeonol is a potent therapy for psoriasis. This study aimed to screen out paeonol-targeted genes in psoriasis and validate the potential of using paeonol for the management of psoriasis.MethodsMicroarray datasets were obtained from the Gene Expression Omnibus. The differentially expressed genes (DEGs) in the lesional skin samples and the overlapping genes between DEGs and paeonol- and psoriasis-related genes were defined as potential targets for psoriasis. After being treated with si-ATG5 and pc-ATG5, human HaCaT cells were treated with 100 ng/ml IL-22 and 10 ng/ml TNF-α with and without paeonol. Cell proliferation, apoptosis, and expression of interleukin (IL)-6, IL-1β, Beclin 1, ATG5, and p62 in HaCaT cells were determined using ESLIA, PCR, and Western blot analysis.ResultsA total of 779 DEGs were identified in the lesional skin samples compared with the non-lesional tissues. The autophagy-related 5 (ATG5) gene was the only gene that overlapped between the DEGs and genes related to paeonol and psoriasis. Cell proliferation, inflammatory cytokines (IL-6 and IL-1β), and ATG5 expression were increased in IL-22/TNF-α-stimulated HaCaT (model) cells compared with control. Paeonol treatment rescued all changes. si-ATG5 transfection increased inflammation and apoptosis in model cells compared with controls. pc-ATG5 prevented IL-22/TNF-α-induced changes in HaCaT cells. Also, si-ATG5 decreased p62 and Beclin 1 proteins, while pc-ATG5 increased them both.ConclusionsATG5-dependent autophagy plays a crucial role in psoriasis. The ATG5 gene might be a therapeutic target for the management of in vitro psoriasis.
| S-EPMC8162242 | biostudies-literature
Project description:Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells. Experiment Overall Design: 4 Samples: 2 replicates of Atg16-hypomorph Paneth cells and 2 replicates of Wildtype Paneth cells.
2008-11-15 | E-GEOD-13512 | biostudies-arrayexpress