# HISTORY 07 May 2016: Updated by: TOUCHUP-v1.18 14 Mar 2016: Updated by: TOUCHUP-v1.12 24 Mar 2016: Updated by: TOUCHUP-v1.15 # molecular_function 20150130: root_PTN000047947 has function cysteine-type endopeptidase activity involved in apoptotic process (GO:0097153) 20150130: Eumetazoa_PTN000825206 has function cysteine-type endopeptidase activity involved in execution phase of apoptosis (GO:0097200) 20140226: node_PTN000825074 has function death effector domain binding (GO:0035877) 20150130: Euteleostomi_PTN000048050 has LOST/MODIFIED function cysteine-type endopeptidase activity involved in apoptotic process (GO:0097153) # cellular_component 20140226: root_PTN000047947 is found in cytoplasm (GO:0005737) 20140228: Euteleostomi_PTN000048050 is found in NLRP3 inflammasome complex (GO:0072559) 20140228: Euteleostomi_PTN000048050 is found in IPAF inflammasome complex (GO:0072557) 20140228: Euteleostomi_PTN000048050 is found in AIM2 inflammasome complex (GO:0097169) 20140228: Catarrhini_PTN000048077 is found in NLRP1 inflammasome complex (GO:0072558) 20140228: Theria _PTN001312222 is NOT found in NLRP3 inflammasome complex (GO:0072559) 20140228: Theria _PTN001312222 is NOT found in IPAF inflammasome complex (GO:0072557) 20140228: Theria _PTN001312222 is NOT found in AIM2 inflammasome complex (GO:0097169) 20140228: Catarrhini_PTN000048077 is NOT found in NLRP3 inflammasome complex (GO:0072559) 20140228: Catarrhini_PTN000048077 is NOT found in IPAF inflammasome complex (GO:0072557) 20140228: Catarrhini_PTN000048077 is NOT found in AIM2 inflammasome complex (GO:0097169) # biological_process 20150130: Eumetazoa_PTN000825206 participates in execution phase of apoptosis (GO:0097194) 20140228: Euteleostomi_PTN000048336 participates in erythrocyte differentiation (GO:0030218) 20140228: Euteleostomi_PTN000048336 participates in neuron differentiation (GO:0030182) 20140228: Euteleostomi_PTN000048336 participates in keratinocyte differentiation (GO:0030216) 20140228: Euteleostomi_PTN000047953 participates in negative regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902042) 20140228: Euteleostomi_PTN000048050 participates in regulation of inflammatory response (GO:0050727) 20140228: Euteleostomi_PTN000048015 participates in intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630) 20140228: Euteleostomi_PTN000047970 participates in extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625) 20140228: Euteleostomi_PTN000047970 participates in macrophage differentiation (GO:0030225) 20140228: Theria _PTN001312222 does NOT participate in regulation of inflammatory response (GO:0050727) # PRUNED 07 May 2016: Homininae_PTN000048229 has been pruned from tree # WARNINGS - THE FOLLOWING HAVE BEEN REMOVED FOR THE REASONS NOTED # NOTES 24 Mar 2016: Homininae_PTN000048229 has been pruned from tree 14 Mar 2016: Homininae_PTN000048229 has been pruned from tree MSA (and therefore tree) is based only on the caspase domain. Two major clades: one includes all human initiator caspases (2, 8, 9, 10), and the other includes both effector caspases (3, 6, 7) and immune-related caspases (1, 4, 5). One minor clade at same level. Each major clade spans bilateria, but not enough evidence to conclude initiator vs effector was ancestral. For example, nearly all extant fly caspases are in the effector clade, but all extant worm caspases are in the initiator clade. The subclade of immune-related caspases (1,4,5,12) spans vertebrates, consistent with its function in acquired immunity. Pruned groups lacking a good alignment to caspase domain, three clades (including human CARD16, PYCARD, PYDC1, CARD18). MOLECULAR FUNCTION: - propagated cys protease to root - loss in several clades: --CFLAR ancestor lost proteolytic activity (verified lost residues), gained function of CASP8 regulator; and human CASP12 (but not other casp12's) has also lost an active site residue and is inactive according to Swiss-Prot CELLULAR COMPONENT: - propagated cytosol to root - gain of inflammasome for CASP1-related clade (lost in casp12, see below) BIOLOGICAL PROCESS - For BP, propagated the following apoptotis-related terms: -- apoptotic process to root -- execution phase of apoptosis to vertebrate subclade of effector clade. Did not propagate for initiator caspases, as these are not part of the execution process (there is one EXP to human CASP8; will challenge). -- intrinsic (casp9,casp2-novel DNA damage pathway) and extrinsic (casp8,casp2-extrinsic ligand withdrawal) apoptotic signaling pathways, regul of extrinsic for CFLAR (interacts with casp8); there was an extrinsic pathway annotation for mouse casp3 (do not propagate, will challenge) -- apoptosis in response to ER stress (casp12)- this one appears to be reacquisition of apoptotic function, as the rest of the clade has an inflammatory role (see below) - Additional non-apoptotic processes: --cell differentiation: noted that there are many annotations to cell type-specific differentiation processes including ---casp3:keratinocyte differentiation, neuron differentiation, erythrocyte differentiation ---casp8:macrophage differentiation --Did not propagate some that sounded apoptosis-independent but upon closer inspection are not: ---neg. reg. of neuromuscular synaptic transmission from PMID 22153373 - Inflammatory processes for 1/12/5/4 subclade, though apparently lost in 12. Propagated the following processes: - 1/12/5/4 subclade lost BP of apoptosis and gained BP of inflammation (CC of inflammasome). PT Feb 2014 Made more specific annotations signaling/execution of apoptosis to the different clades as described above. PG Jan 30 2015 # REFERENCE Annotation inferences using phylogenetic trees The goal of the GO Reference Genome Project, described in PMID 19578431, is to provide accurate, complete and consistent GO annotations for all genes in twelve model organism genomes. To this end, GO curators are annotating evolutionary trees from the PANTHER database with GO terms describing molecular function, biological process and cellular component. GO terms based on experimental data from the scientific literature are used to annotate ancestral genes in the phylogenetic tree by sequence similarity (ISS), and unannotated descendants of these ancestral genes are inferred to have inherited these same GO annotations by descent. The annotations are done using a tool called PAINT (Phylogenetic Annotation and INference Tool).