APO-SYS consortium Annual Meeting

1. APO-SYS consortium Annual Meeting Pablo Porras Millán, IntAct and GO Scientific Curator at EBI

2. Background: the Gene Ontology • The Gene Ontology (GO) project aims at standardizing the representation of gene and gene product attributes across species and databases. GO provides a controlled vocabulary of terms to describe gene product characteristics. • Biological Process: e.g. GO:0006915 apoptosis • Molecular Function: e.g. GO:0043028 caspase regulator activity • Cellular Component: e.g. GO:0043293 apoptosome • Relationships exist to link these classes when necessary http://www.geneontology.org/

3. Background: the Gene Ontology • GO covers normal, natural processes • No pathological processes or disease states; e.g. “oncogenesis” is not a valid GO term because causing cancer is not the normal function of any gene. • GO terms must be species-independent • Taxon restrictions can be introduced when needed; e.g. “salivary gland cell autophagic cell death” is restricted to Arthropoda • GO terms represent characteristics of gene products • No gene products themselves; e.g. no “Notch activity”, while“Notch binding” is fine • GO is NOT a nomenclature system

4. New deliverable “Improved GO annotation for Apoptosis” Discussions result, mainly at APO-SYS workshop Stockholm, 2009: GO annotation and GO-based tools are a promising method to integrate data across data types BUT: The Gene Ontology has significant deficits in the areas relevant for APO-SYS. Aims and deliverables: The aim of this project is to overhaul all the terms related to apoptosis in GO, mainly processes. Term phrasing and tree structures will be standardized, and new terms will be added with the aim of giving a broad coverage for all applicable species. Release of the fully revised and extended GO “Apoptosis” branch GO annotation of at least 125 apoptosis-relevant gene products based on information from at least 200 publications recommended by APO-SYS domain experts.

5. Cell death: current state of the ontology

6. Cell death: new ontology structure • Cell death (GO:0008219) • (I) Programmed cell death (GO:0012501) • (I) Autophagic cell death, cornification, pyroptosis • Under consideration: entosis, parthanatos and netosis. • (I) Apoptotic process(GO:0006915) • (I) Necrotic cell death • (I) Programmed necrotic cell death • (I) Necroptosis • (I) Cytolisis • (R) Regulatory terms

7. Apoptosis in GO GO:0006915 “apoptosis” will be “apoptotic process”

8. Apoptosis in GO: current state of the ontology

9. A provisional ontology structure for apoptosis • Apoptotic process (GO:0006915) • (P) Apoptotic signaling pathway • (P) Execution phase of apoptotic process • (P) Cellular component disassembly involved in apoptosis (GO:0006921) • (P) Apoptotic mitochondrial changes (GO:0008637) • (I) Tissue, cell type and event-specific apoptosis related terms (e.g.- endothelial cell apoptosis, GO:0072577; anoikis, GO:0043276) • (R) Regulatory terms

10. GO:NEW apoptotic signaling pathway • (I) Extrinsic apoptotic signaling pathway • (I) Intrinsic apoptotic signaling pathway • (P) Mitochondrial outer membrane permeabilization (MOMP) • (I) Granzyme-mediated apoptotic signaling pathway • (I) Hormone-mediated apoptotic signaling pathway • (R) Regulatory terms • (I) Other terms tissue/cell type specific

11. Apoptotic signaling pathway • Extrinsic apoptotic signaling pathway • (I) EASP initiated through ligand binding • Covers death-domain receptors and other TNF receptors that lack a death domain (PMID: 21525013) • (P) Death domain-mediated complex assembly (GO:0071550) • (I) EASP initiated through ligand withdrawal • Covers dependence receptors • Intrinsic apoptotic signaling pathway • (I) Caspase-dependent IASP • Apoptosome assembly (GO:0039107) • (I) Caspase-independent IASP • Problematic: Based in experimental observations using caspase inhibitors. Does this really happen in physiological situations?

12. Execution phase of the apoptotic process (GO:0039112) • (P) Apoptotic nuclear change (GO:0030262) • (P) Cleavage of cytoskeletal proteins involved in apoptosis (GO:0006923) • (P) Phosphatidylserine exposure on apoptotic cell surface (GO:0070782) • Mitochondrial terms: Do they belong here? • (P) Mitochondrial fragmentation involved in apoptosis (GO:0043653) • (P) Release of matrix enzymes from mitochondria (GO:0032976) • (P) Cell junction disruption (new term?) • References? • (P) Effector caspases (new terms)

13. Caspase terms issues • GO:0030693, “caspase activity” was obsoleted because it represents gene product(s) and because the distinction from other types of proteases is outside the scope of GO • All process terms containing it renamed to “cysteine-type endopeptidase activity involved in apoptotic process” • Regulatory and other children terms are renamed accordingly • The old terms stay to allow the user to find the correct terms • Terms for initiator and effector caspases: • GO:NEW cysteine-type endopeptidase activity involved in apoptotic signaling pathway • Broad synonym: initiator caspase • GO:NEW cysteine-type endopeptidase activity involved in execution phase of apoptotic process • Broad synonym: effector caspase

14. Apoptosis GO project • Annotation progress: around 20 papers curated for IntAct and GO, 35 relevant genes annotated (around 1 month worktime). • Apoptosis GO wiki page: http://wiki.geneontology.org/index.php/Apoptosis • Please email your suggestions/comments to • Pablo Porras Millan pporras@ebi.ac.uk • Paola Roncaglia paola@ebi.ac.uk • Emily Dimmer edimmer@ebi.ac.uk

15. A final request… Would you like to spend a couple of days discussing apoptosis ontology in Hinxton?