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Schema Name ATG16L1 and Microbiome Interaction schema for Crohn's disease
Accession MS020500027.6
Gene(s) ATG16L1
Schema Caption Effect of ATG16L1 genetic variant interaction with both commensal and pathogenic microbiomes.
Schema Description This schema is addressing the effect of a common ATG16L1 genetic variant rs2241880 (T300A) during the processing of microbiomes in the cell, be it commensal or pathogenic. In general, how defects in ATG16L1 is contributing to Crohn's disease, we have a separate schema for that "ATG16L1 Schema for Crohn's disease". Defective ATG16L1 has defective autophagy machinery, both canonical and non-canonical. Here we show how defective non-canonical autophagy fails to recognize commensal bacteria B. fragilis outer membrane vesicle (OMV) and thereby fails to suppress the inflammation signal even for a commensal bacteria (pmid: 27230380). This schema also includes the effect of a pathogenic bacteria S. typhimurium in the paneth cell and how defective autophagy machinery fails to combat that infection (pmid: 28751470). Essentially, when this infection occurs, it shuts down the normal secretion of anti-microbial peptide lysozyme from the paneth cell, by destroying the Golgi apparatus. The paneth cell then chose another alternative pathway to re-route lysozyme secretion. ER stress in paneth cell, caused by this infection, together with IL-22 from activated immune cell ILC3 and activated dendritic cell, attempt to use secretory autophagy to secret lysozyme - if the autophagy machinery is defective due to the presence of this T300A variant in ATG16L1, then re-routing of lysozyme secretion cannot work - cannot clear the pathogenic microbiome load from the cell and induce Crohn's disease risk.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) John Moult
Last Modified Fri Aug 10 2018 15:54:05 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: SSP7
Stage: Cell
SSP Class: Other
Other SSP Class: T-cell Response
Modifier: Decreased
Ontology:
SSP Instance: Less Induction of CD4+Foxp3+ IL-10 Tregs
Confidence Score: 5
Comment: With defective sensing of bacterial OMV, ATG16L1 T300A variant fails to induce anti-inflammatory IL-10 expression from CD4+ Foxp3+ T regulatory cells.
For Evidence: PMID:27230380, PMID:28847720
Against Evidence:
Component ID: SSP6
Stage: Cell
SSP Class: Other
Other SSP Class: Non-canonical Autophagosome Abundance
Modifier: Decreased
Ontology:
SSP Instance: Lack of LC3 associated phagocytosis
Confidence Score: 3
Comment: OMVs preferentially utilize the non-canonical autophagy pathway LAP (LC3 associated phagocytosis).
For Evidence: PMID:27230380
Against Evidence:
Component ID: SSP15
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: SSP8
Stage: Cell
SSP Class: Other
Other SSP Class: Animicrobial Peptide Abundance
Modifier: Decreased
Ontology:
SSP Instance: Lysozyme from Paneth cell
Confidence Score: 5
Comment: Due to invasive pathogen infection, regular secretion of aniti-microbial proteins, like lysozyme from the paneth cells gets obstructed.
For Evidence: PMID:28751470
Against Evidence:
Component ID: SSP10
Stage: Cell
SSP Class: Other
Other SSP Class: ER Stress
Modifier: Increased
Ontology:
SSP Instance: Pathogen induced stress
Confidence Score: 5
Comment: Damage of Golgi apparatus due to infection causes endoplasmic reticulum (ER) stress. There will be less ER-to-Golgi protein trafficking which contributes to ER stress via protein overload.
For Evidence: PMID:28751470, PMID:19727664
Against Evidence:
Component ID: SSP11
Stage: Cell
SSP Class: Other
Other SSP Class: Immune Cell Abundance
Modifier: Increased
Ontology:
SSP Instance: Innate lymphoid cell type 3 (ILC3)
Confidence Score: 5
Comment: Activated dendritic cell signaling by TLRs via MyD88-dependent pathway triggers activation of another type of immune cell, innate lymphoid cell type 3 (ILC3).
For Evidence: PMID:28751470, PMID:28883062
Against Evidence:
Component ID: SSP14
Stage: Cell
SSP Class: Other
Other SSP Class: Anti-microbial Peptide Abundance
Modifier: Decreased
Ontology:
SSP Instance: Re-routed Lysozyme
Confidence Score: 5
Comment: Secretory autophagy is disrupted in Paneth cells of mice with ATG16L1 T300A variant. As a result re-routed lysozyme cannot secret from the paneth cell.
For Evidence: PMID:28883062, PMID:28751470
Against Evidence:
Component ID: SSP12
Stage: Protein
SSP Class: Post-Translational Modified Protein Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: PERK, EIF2α
Confidence Score: 5
Comment: Upregulated CHOP expression and phosphorylated PERK and eIF2α, together with IL-22, facilitates packaging of lysozyme in LC3+ vesicles - autophagosome. In presence of ATG16L1 T300A, this autophagosome formation is impaired.
For Evidence: PMID:24821797, PMID:28751470, PMID:28883062
Against Evidence:
Component ID: SSP13
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: IL-22
Confidence Score: 5
Comment: IL-22 is one of the required component which licenses ATG16L1 for secretory autophagy to combat the infection.
For Evidence: PMID:24821797, PMID:28751470, PMID:28883062
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: MM7
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology: GO
Mechanism Instance:
Confidence Score: 5
Comment: Due to decreased IL-10 induction, inflammation will increase.
For Evidence: PMID:27230380, PMID:28847720
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: Sensing
Modifer: NA
Ontology:
Mechanism Instance: Defective sensing of bacterial OMV
Confidence Score: 5
Comment: ATG16L1 T300A variant fails to respond to bacterial OMVs (outer membrane vesicles).
For Evidence: PMID:27230380
Against Evidence:
Component ID: MM8
Mechanism Class Name:
Other Mechanism Class Name: Golgi fragmentation
Modifer: NA
Ontology:
Mechanism Instance: Golgi fragmentation of Paneth cells
Confidence Score: 5
Comment: S. Typhimurium infection causes Golgi fragmentation of Paneth cells, which disrupts ER-Golgi complex, breakdown of Golgi apparatus.
For Evidence: PMID:28751470
Against Evidence:
Component ID: MM10
Mechanism Class Name: Activation of PERK branch of ER stress
Other Mechanism Class Name:
Modifer: NA
Ontology: GO
Mechanism Instance: Activation of PERK branch of ER stress
Confidence Score: 5
Comment: Bacterial pathogen activates the PERK/eIF2α/CHOP branch of the ER stress response. This step includes upregulation of CHOP expression, phosphorylation of PERK and eIF2α.
For Evidence: PMID:28883062, PMID:28751470
Against Evidence:
Component ID: MM9
Mechanism Class Name: Activation of dendritic cell signaling by TLRs
Other Mechanism Class Name:
Modifer: NA
Ontology: GO
Mechanism Instance: Activation of dendritic cell signaling by TLRs
Confidence Score: 5
Comment: Bacterial pathogen as recognized by TLRs, activates dendritic cells via MyD88-dependent pathway and trigger IL-22 secretion from another type of immune cell, innate lymphoid cell type 3 (ILC3).
For Evidence: PMID:28883062, PMID:28751470
Against Evidence:
Component ID: MM11
Mechanism Class Name: secretion of IL-22
Other Mechanism Class Name:
Modifer: NA
Ontology: GO
Mechanism Instance: Increased secretion of IL-22
Confidence Score: 5
Comment: ILC3 secrets IL-22 which acts on Paneth cells to control secretory autophagy of lysozyme
For Evidence: PMID:28883062, PMID:28751470
Against Evidence:
Component ID: MM13
Mechanism Class Name:
Other Mechanism Class Name: Secretion rate
Modifer: Decreased
Ontology: GO
Mechanism Instance: Decreased secretion from Paneth cell
Confidence Score: 5
Comment: Bacterial pathogen induced IL-22 secretion from ILC3s together with activated PERK branch of ER stress will affect the lysozyme release via ATG16L1 T300A variant dependent secretory autophagy in Paneth cells.
For Evidence: PMID:28883062, PMID:28751470
Against Evidence:
Component ID: MM14
Mechanism Class Name: Microbial clearance
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Decreased Microbial clearance
Confidence Score: 5
Comment: ATG16L1 T300A variant fails to clear the infection from the paneth cell.
For Evidence: PMID:28883062, PMID:28751470
Against Evidence:
Component ID: MM5
Mechanism Class Name:
Other Mechanism Class Name: Sensing
Modifer: Decreased
Ontology:
Mechanism Instance: Decreased non-canonical autophagy
Confidence Score: 3
Comment: For ATG16L1 T300A variant, the non-canonical autophagy pathway LAP (LC3 associated phagocytosis) gets affected. However this variant is not directly present on the active site of WD40 domain [29317426], it is hypothesized that due to increased cleavage rate of ATG16L1 for T300A, it affects WD40 domain dependent LAP - so we used medium confidence here.
For Evidence: PMID:27230380, PMID:29431607, PMID:29317426
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Environmental Factor Annotations
Component ID: EF1
Annotation Text: B. fragilis
Comment: The human commensal bacteria B. fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs).
For Evidence: PMID:27230380
Against Evidence:
Component ID: EF4
Annotation Text: S. typhimurium
Comment: Infection with intestinal bacterial pathogen Salmonella enterica serovar Typhimurium.
For Evidence: PMID:28883062, PMID:28751470
Against Evidence:
Therapeutic Interventions Annotations