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Schema Name ATG16L1 Schema for Crohn's disease
Accession MS020800050.2
Gene(s) ATG16L1, NOD2, TLR4
Schema Caption Effect of ATG16L1 genetic variant towards Crohn's disease risk
Schema Description This schema is addressing the effect of a common genetic variant rs2241880 (T300A) in ATG16L1 towards Crohn's disease risk. For microbiome interactions, we have a separate schema "ATG16L1 and Microbiome Interaction schema for Crohn's disease". In this schema, we address the role of this genetic variant in ATG16L1 for ER stress response in Paneth cell, inflammation in macrophages, defective MHC II presentation in dendritic cell and also defective autophagy machinery. As NOD2 and TLR4 take part in recognizing bacterial fragments and then use autophagy machinery to process the downstream effects, defect in ATG16L1 affects their role also in Crohn's disease. Also, we can observe a presence of a feedback loop here, as more ER stress will lead to more cleavage of defective ATG16L1 and thereby fails to inhibit stress signal, increasing more ER stress.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) Lipika R. Pal, John Moult
Last Modified Fri Aug 10 2018 15:53:56 GMT-0400 (Eastern Daylight Time)
Sub-state Perturbation (SSP) Annotations
Component ID: SSP1
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs2241880 in ATG16L1
Confidence Score: 5
Comment: ATG16L1 rs2241880 is an established GWAS marker for increase in Crohn’s disease risk. As these are GWAS marker information, where relationship with increasing disease risk is based on allele frequency, so SNV can be in either heterozygous (HET) or homozygous (HOM) mode.
For Evidence: PMID:23128233
Against Evidence:
Component ID: SSP2
Stage: Protein
SSP Class: Missense Variant
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: NP_110430: p.Thr300Ala in ATG16L1
Confidence Score: 5
Comment: This is a missense variant Thr300Ala, which is located at exon 9, beginning of C-terminal WD40 domains.
For Evidence: PMID:24553140
Against Evidence:
Component ID: SSP4
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class: Cell stress
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: Activated Caspases
Confidence Score: 5
Comment: Cellular stress results in caspase 3 and/or 7 activation.
For Evidence: PMID:19626005
Against Evidence:
Component ID: SSP3
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Stress
Modifier: NA
Ontology:
SSP Instance: Cellular/metabolic stress, or infection
Confidence Score: 5
Comment: Cell stress can be generated from ER stress or metabolic stress like nutrient deprivation or infection. Deletion of the unfolded protein response transcription factor XBP1 in intestinal epithelial cells results in ER stress, Paneth cell impairment.
For Evidence: PMID:24553140, PMID:24089213, PMID:18775308
Against Evidence:
Component ID: SSP5
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: ATG16L1 T300A
Confidence Score: 5
Comment: ATG16L1 T300A variant has increased cleavage rate by caspase 3, resulting into decreased abundance of full length ATG16L1 T300A form.
For Evidence: PMID:24821797
Against Evidence:
Component ID: SSP6
Stage: Cell
SSP Class: Other
Other SSP Class: Pro-inflammatory UPR
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory NF-kB
Confidence Score: 5
Comment: NF-kB gets activated due to UPR.
For Evidence: PMID:28883062, PMID:28082357, PMID:24089213
Against Evidence:
Component ID: SSP8
Stage: Cell
SSP Class: Other
Other SSP Class: Activated Cytokines Abundance
Modifier: Increased
Ontology:
SSP Instance: IL-1β, IL-18
Confidence Score: 5
Comment: LPS stimulated macrophages produce increased amount of pro-inflammatory cytokines via Caspase-1 activation. ATG16L1 T300A variant fails to regulate this Caspase-1 activation.
For Evidence: PMID:18849965, PMID:28741645, PMID:28614717
Against Evidence:
Component ID: SSP12
Stage: Phenotype
SSP Class: Other
Other SSP Class: DIsease Risk
Modifier: Increased
Ontology:
SSP Instance: Ileal Crohn's disease
Confidence Score: 5
Comment: ATG16L1 T300A variant is uniquely associated with ileal Crohn's disease.
For Evidence: PMID:17200669, PMID:17484864
Against Evidence:
Component ID: SSP10
Stage: Cell
SSP Class: Other
Other SSP Class: Defective Autophagosome Abundance
Modifier: NA
Ontology:
SSP Instance: Autophagosome complex
Confidence Score: 5
Comment: Secretory autophagy is disrupted in Paneth cells of mice with ATG16L1 T300A variant.
For Evidence: PMID:19966812, PMID:22449030
Against Evidence:
Component ID: SSP7
Stage: Protein
SSP Class: Other
Other SSP Class: Stimulated Protein Abundance
Modifier: NA
Ontology:
SSP Instance: TLR4 by bacterial LPS
Confidence Score: 5
Comment: TLR4 will be stimulated upon recognizing LPS and move from cell surface to endosome in macrophages.
For Evidence:
Against Evidence:
Component ID: SSP9
Stage: Protein
SSP Class: Other
Other SSP Class: Stimulated Protein Abundance
Modifier: NA
Ontology:
SSP Instance: NOD2 by bacterial MDP
Confidence Score: 5
Comment: NOD2 will be activated upon recognizing MDP and subsequent cleavage will take place. This activated NOD2 will recruit ATG16L1 for autophagy.
For Evidence:
Against Evidence:
Biomarker(s) Annotations
Mechanism Module (MM) Annotations
Component ID: MM1
Mechanism Class Name: Synthesis Rate
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Protein synthesis
Confidence Score: 5
Comment: Protein synthesis is unaffected by presence of this SNV.
For Evidence:
Against Evidence:
Component ID: MM4
Mechanism Class Name: cleavage rate by Caspase3
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance: Increased cleavage rate by Caspase3
Confidence Score: 5
Comment: The presence of this variant leads to increased cleavage rate by caspase3 which is abundant due to cell stress.
For Evidence: PMID:24553140
Against Evidence:
Component ID: MM3
Mechanism Class Name:
Other Mechanism Class Name: Cell stress response
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Cell stress response will be induced.
For Evidence: PMID:24553140
Against Evidence:
Component ID: MM5
Mechanism Class Name: Accumulation of IRE1α clusters & increased UPR signaling
Other Mechanism Class Name:
Modifer: NA
Ontology: GO
Mechanism Instance: Accumulation of IRE1α clusters & increased UPR signaling
Confidence Score: 5
Comment: IRE1α forms homodimers upon ER stress, increasing to large clusters with persistent ER stress. A selective ATG16L1 dependent autophagy process is required to remove these clusters and terminate the ER stress induced signaling. Patients with ATG16L1 T300A variant accumulate IRE1α in Paneth cells. Upon accumulation of these clusters, inflammation signal gets turned on. At this stage this Stress signal is acting as a feedback loop, where more Caspase 3 will be activated and more cleavage of ATG16L1 will happen and then again it will fail to inhibit Stress signal.
For Evidence: PMID:28883062, PMID:24657016, PMID:28082357, PMID:24089213
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology: GO
Mechanism Instance:
Confidence Score: 5
Comment: Pro-inflammatory UPR will increase inflammation
For Evidence: PMID:28883062, PMID:24089213
Against Evidence:
Component ID: MM8
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology: GO
Mechanism Instance:
Confidence Score: 5
Comment: Activated IL-1β and IL-18 will increase inflammation
For Evidence: PMID:18849965, PMID:22449030, PMID:28741645
Against Evidence:
Component ID: MM7
Mechanism Class Name: removal of ROS & inflammasome activation in macrophages
Other Mechanism Class Name:
Modifer: NA
Ontology: GO
Mechanism Instance: Decreased removal of ROS & inflammasome activation in macrophages
Confidence Score: 5
Comment: Lack of removal of mitochondrial ROS production by defective autophagy leads to NLRP3 mediated caspase-1 activation. Following stimulation with LPS, a ligand for TLR4, macrophages activates Caspase-1 via induction of TRIF (Toll/IL-1 receptor domain-containing adaptor inducing IFN-β). Regulation of inflammasome activation by autophagy can occur in multiple ways, through either removal of endogenous inflammasome activators or removal of inflammasomes and their downstream cytokines directly, IL-1β.
For Evidence: PMID:18849965, PMID:21124315, PMID:28741645, PMID:24472848
Against Evidence:
Component ID: MM9
Mechanism Class Name: protein protein interaction for autophagosome complex in dendritic cell
Other Mechanism Class Name:
Modifer: NA
Ontology: NCIT
Mechanism Instance: Decreased protein protein interaction for autophagosome complex in dendritic cell
Confidence Score: 5
Comment: NOD2 gets stimulated in presence of bacterial MDP (muramyl-dipeptide). MDP stimulated NOD2 induces autophagy in dendritic cells.
For Evidence: PMID:19966812, PMID:22449030
Against Evidence:
Component ID: MM10
Mechanism Class Name: Defective MHC- II presentation to CD4+ T cells
Other Mechanism Class Name:
Modifer: Decreased
Ontology: GO
Mechanism Instance: Defective MHC- II presentation to CD4+ T cells
Confidence Score: 5
Comment: Activated IL-1β and IL-18 will increase inflammation
For Evidence: PMID:19966812, PMID:22449030
Against Evidence:
Component ID: MM11
Mechanism Class Name: Defective canonical autophagy
Other Mechanism Class Name:
Modifer: Decreased
Ontology: GO
Mechanism Instance: Defective canonical autophagy
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Environmental Factor Annotations
Therapeutic Interventions Annotations
Component ID: TT1
Annotation Text: InflammasomeInhibitor
Comment: NLRP3 inhibitor or caspase-1 inhibitor and decreasing ROS production as potential therapeutic target for Crohn's disease / IBD.
For Evidence: PMID:28155620
Against Evidence: