id: MODULE:c5a_signaling title: Complement component C5a signaling pathway module description: >- Proteolytic cleavage of secreted complement C5 by C3/C5 convertases (or granzyme K) in the extracellular region releases the 74-residue C5a anaphylatoxin, which engages the seven-transmembrane complement receptors C5aR1 (CD88) and C5aR2 (C5L2) at the plasma membrane of myeloid leukocytes, endothelial cells, and other target cells. C5a binding to C5aR1 activates pertussis-toxin-sensitive heterotrimeric Gi proteins (exemplified by GNAI2) and beta-arrestins, whereas C5a binding to the non-G-protein-coupled receptor C5aR2 selectively recruits beta-arrestins to modulate C5aR1 signaling. Together these steps execute the complement component C5a signaling pathway (GO:0038178) and drive PI3Kgamma (PIK3CG)- and RhoA-dependent myeloid leukocyte chemotaxis (GO:0006935) and degranulation. status: DRAFT evidence: - source_id: GO:0038178 title: complement component C5a signaling pathway statement: >- The module is grounded in the GO biological process term for complement component C5a signaling pathway (GO:0038178: the series of molecular signals initiated by complement component C5a binding to a C5a receptor on the surface of a target cell). - source_id: PMID:36806352 title: Mechanism of activation and biased signaling in complement receptor C5aR1. supporting_text: >- The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and β-arrestin signaling pathways. statement: >- Establishes C5a binding to C5aR1 and downstream G-protein (Gi) and beta-arrestin signaling. - source_id: PMID:37169960 title: Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins. supporting_text: >- The complement receptors C3aR and C5aR1, whose signaling is selectively activated by anaphylatoxins C3a and C5a, are important regulators of both innate and adaptive immune responses. statement: >- Resolves the structural basis of anaphylatoxin C5a recognition and Gi coupling by C5aR1. - source_id: PMID:37852260 title: Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors. supporting_text: >- The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. statement: >- Resolves the molecular basis of anaphylatoxin C5a recognition and biased signaling across complement receptors. - source_id: PANTHER:PTN002605305 title: PAINT node PTN002605305 for complement C5 statement: >- Local PAINT IBD node in PTHR11412 with propagated terms P:GO:0006935, P:GO:0006958; PAINT date 20260729. - source_id: PANTHER:PTN000026392 title: PAINT node PTN000026392 for G protein alpha subunits (GNAI2) statement: >- Local PAINT IBD node in PTHR10218 with propagated terms C:GO:0005737, C:GO:0005834, F:GO:0003925, P:GO:0007188; PAINT date 20260828. - source_id: PANTHER:PTN000005674 title: PAINT node PTN000005674 for PIK3CG statement: >- Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005886, F:GO:0016303, F:GO:0035005, P:GO:0043491; PAINT date 20240205. - source_id: PANTHER:PTN000632671 title: PAINT node PTN000632671 for RHOA statement: >- Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005886, F:GO:0003924, F:GO:0005525, P:GO:0007015, P:GO:0007165; PAINT date 20260529. notes: >- Curated signaling-pathway module for the complement component C5a signaling pathway (GO:0038178) built with PANTHER FAMILY/subfamily selectors, explicit molecular functions, biological processes, and cellular locations across the C5a anaphylatoxin ligand (C5, PANTHER:PTHR11412:SF83), the complement C5a receptors C5AR1 (PANTHER:PTHR24225:SF29) and C5AR2 (PANTHER:PTHR24225:SF1), heterotrimeric Gi alpha subunit GNAI2 (PANTHER:PTHR10218:SF73), and downstream chemotaxis effectors PIK3CG (PANTHER:PTHR10048) and RHOA (PANTHER:PTHR24072). module: id: c5a_signaling label: Complement component C5a signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: complement component C5a signaling pathway term: id: GO:0038178 label: complement component C5a signaling pathway description: >- The series of molecular signals initiated by complement component C5a binding to a C5a receptor (C5aR1 or C5aR2) on the surface of a target cell, and ending with the regulation of a downstream cellular process. context: taxa: - preferred_term: Euteleostomi term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: C5a ligand-receptor engagement node: id: c5a_receptor_engagement label: C5a anaphylatoxin receptor engagement module_type: REGULATORY_STEP description: >- The C5a anaphylatoxin fragment released by cleavage of complement C5 engages the seven-transmembrane complement receptors C5aR1 (CD88) and C5aR2 (C5L2) at the target cell plasma membrane via a two-site recognition mechanism (an N-terminal acidic region docking the C5a helical core and an orthosteric pocket binding the C5a C-terminal octapeptide). annotons: - id: c5_c5a_anaphylatoxin_ligand label: C5 (C5a anaphylatoxin) ligand participant: selector_type: FAMILY family: preferred_term: Complement C5 subfamily term: id: PANTHER:PTHR11412:SF83 label: COMPLEMENT C5 representative_members: - preferred_term: C5 term: id: UniProtKB:P01031 label: 'Complement C5 [Cleaved into: Complement C5 beta chain; Complement C5 alpha chain; C5a anaphylatoxin; Complement C5alpha'' chain]' ancestral_nodes: - preferred_term: PAINT node PTN002605305 for complement C5 term: id: PANTHER:PTN002605305 label: PTN002605305 description: >- Local PAINT IBD node in PTHR11412 with propagated terms P:GO:0006935, P:GO:0006958; PAINT date 20260729. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002605305 in PTHR11412. evidence: - source_id: file:interpro/panther/PTHR11412/PTHR11412-review.yaml title: PTHR11412 PANTHER family review statement: >- PTHR11412 review scopes GO:0038178 (complement component C5a signaling pathway) to PANTHER:PTHR11412:SF83 (COMPLEMENT C5) and flags PAINT node PTN008967461 GO:0008009 (chemokine activity) as WRONG_NODE. function: preferred_term: G protein-coupled receptor binding term: id: GO:0001664 label: G protein-coupled receptor binding processes: - preferred_term: complement component C5a signaling pathway term: id: GO:0038178 label: complement component C5a signaling pathway - preferred_term: cell chemotaxis term: id: GO:0060326 label: cell chemotaxis locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Precursor of the secreted 74-residue C5a anaphylatoxin peptide that directly binds and activates C5aR1 and C5aR2 to initiate the complement component C5a signaling pathway and myeloid leukocyte chemotaxis. evidence: - source_id: PMID:36806352 title: Mechanism of activation and biased signaling in complement receptor C5aR1. supporting_text: >- The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and β-arrestin signaling pathways. statement: >- Demonstrates C5a binding and activation of C5aR1 to initiate downstream G-protein and beta-arrestin signaling. - id: c5ar1_c5a_receptor_1 label: C5AR1 complement C5a receptor 1 participant: selector_type: FAMILY family: preferred_term: C5a anaphylatoxin chemotactic receptor 1 subfamily term: id: PANTHER:PTHR24225:SF29 label: C5A ANAPHYLATOXIN CHEMOTACTIC RECEPTOR 1 representative_members: - preferred_term: C5AR1 term: id: UniProtKB:P21730 label: 'C5a anaphylatoxin chemotactic receptor 1 (C5a-R) (C5aR) (CD antigen CD88)' evidence: - source_id: PMID:36806352 title: Mechanism of activation and biased signaling in complement receptor C5aR1. supporting_text: >- The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and β-arrestin signaling pathways. statement: >- Establishes C5AR1 as the canonical G-protein-coupled and beta-arrestin-coupled complement C5a receptor. function: preferred_term: complement receptor activity term: id: GO:0004875 label: complement receptor activity processes: - preferred_term: complement component C5a signaling pathway term: id: GO:0038178 label: complement component C5a signaling pathway - preferred_term: chemotaxis term: id: GO:0006935 label: chemotaxis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Canonical seven-transmembrane complement C5a receptor (CD88) on myeloid leukocytes and endothelial cells that transduces C5a binding into heterotrimeric Gi activation and beta-arrestin recruitment. evidence: - source_id: PMID:37169960 title: Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins. supporting_text: >- The complement receptors C3aR and C5aR1, whose signaling is selectively activated by anaphylatoxins C3a and C5a, are important regulators of both innate and adaptive immune responses. statement: >- Resolves C5a-bound C5aR1 in complex with heterotrimeric Gi. - id: c5ar2_c5a_receptor_2 label: C5AR2 complement C5a receptor 2 participant: selector_type: FAMILY family: preferred_term: C5a anaphylatoxin chemotactic receptor 2 subfamily term: id: PANTHER:PTHR24225:SF1 label: C5A ANAPHYLATOXIN CHEMOTACTIC RECEPTOR 2 representative_members: - preferred_term: C5AR2 term: id: UniProtKB:Q9P296 label: 'C5a anaphylatoxin chemotactic receptor 2 (Complement component 5a receptor 2) (G-protein coupled receptor 77)' evidence: - source_id: PMID:36806352 title: Mechanism of activation and biased signaling in complement receptor C5aR1. supporting_text: >- The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and β-arrestin signaling pathways. statement: >- Establishes C5a receptor family signaling through G-protein and beta-arrestin pathways. function: preferred_term: complement receptor activity term: id: GO:0004875 label: complement receptor activity processes: - preferred_term: complement component C5a signaling pathway term: id: GO:0038178 label: complement component C5a signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Non-G-protein-coupled seven-transmembrane C5a receptor (C5L2/GPR77) that binds C5a and C5a-desArg to selectively recruit beta-arrestins and modulate C5aR1-driven signaling. evidence: - source_id: PMID:36806352 title: Mechanism of activation and biased signaling in complement receptor C5aR1. supporting_text: >- The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and β-arrestin signaling pathways. statement: >- Supports C5a receptor engagement and beta-arrestin pathway activation. - order: 2 role: heterotrimeric g protein coupling node: id: gi_protein_coupling label: Gi protein coupling module_type: REGULATORY_STEP description: >- Agonist-activated C5aR1 acts as a guanine nucleotide exchange factor (GEF) for pertussis-toxin-sensitive Gi/o heterotrimeric G proteins at the inner leaflet of the plasma membrane, dissociating Galpha_i-GTP and Gbetagamma dimers. annotons: - id: gnai2_gnai2_alpha_subunit label: GNAI2 alpha subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(i) subunit alpha-2 subfamily term: id: PANTHER:PTHR10218:SF73 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(I) SUBUNIT ALPHA-2 representative_members: - preferred_term: GNAI2 term: id: UniProtKB:P04899 label: 'Guanine nucleotide-binding protein G(i) subunit alpha-2 (EC 3.6.5.-) (Adenylate cyclase-inhibiting G alpha protein)' ancestral_nodes: - preferred_term: PAINT node PTN000026392 for G protein alpha subunits term: id: PANTHER:PTN000026392 label: PTN000026392 description: >- Local PAINT IBD node in PTHR10218 with propagated terms C:GO:0005737, C:GO:0005834, F:GO:0003925, P:GO:0007188; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000026392 in PTHR10218. evidence: - source_id: PANTHER:PTN000026392 title: PAINT node PTN000026392 for GNAI2 statement: >- Supports heterotrimeric G protein activity (GO:0003925) in PTHR10218. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: complement component C5a signaling pathway term: id: GO:0038178 label: complement component C5a signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Inhibitory heterotrimeric G protein alpha subunit coupled to C5aR1 that exchanges GDP for GTP upon C5a binding, inhibiting adenylyl cyclase and releasing Gbetagamma dimers to activate PI3Kgamma and PLCbeta. evidence: - source_id: PMID:36806352 title: Mechanism of activation and biased signaling in complement receptor C5aR1. supporting_text: >- The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and β-arrestin signaling pathways. statement: >- Resolves direct coupling of C5a-activated C5aR1 to heterotrimeric Gi. - order: 3 role: C5a chemotaxis effector output node: id: c5a_chemotaxis_effector_output label: C5a chemotaxis and effector output module_type: REGULATORY_STEP description: >- PI3Kgamma and Rho-family GTPase effectors downstream of C5aR1-Gi activation generate leading-edge PtdIns(3,4,5)P3 gradients and coordinate actomyosin polarization to drive myeloid leukocyte chemotaxis and degranulation. annotons: - id: pik3cg_pi3k_gamma_catalytic_branch label: PI3K gamma catalytic branch participant: selector_type: FAMILY family: preferred_term: PI3K gamma catalytic branch family/ortholog group term: id: PANTHER:PTHR10048 label: PHOSPHATIDYLINOSITOL KINASE representative_members: - preferred_term: PIK3CG term: id: UniProtKB:P48736 label: 'Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PI3-kinase subunit gamma) (PI3K-gamma) (PI3Kgamma) (PtdIns-3-kinase subunit gamma) (EC 2.7.1.137) (EC 2.7.1.153) (EC 2.7.1.154) (Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma) (PtdIns-3-kinase subunit p110-gamma) (p110gamma) (Phosphoinositide-3-kinase catalytic gamma polypeptide) (Serine/threonine protein kinase PIK3CG) (EC 2.7.11.1) (p120-PI3K)' ancestral_nodes: - preferred_term: PAINT node PTN000005674 for PIK3CG term: id: PANTHER:PTN000005674 label: PTN000005674 description: >- Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005886, F:GO:0016303, F:GO:0035005, P:GO:0043491; PAINT date 20240205. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000005674 in PTHR10048. evidence: - source_id: PANTHER:PTN000005674 title: PAINT node PTN000005674 for PIK3CG statement: >- Supports 1-phosphatidylinositol-3-kinase activity (GO:0016303) at the plasma membrane (GO:0005886). function: preferred_term: 1-phosphatidylinositol-3-kinase activity term: id: GO:0016303 label: 1-phosphatidylinositol-3-kinase activity processes: - preferred_term: complement component C5a signaling pathway term: id: GO:0038178 label: complement component C5a signaling pathway - preferred_term: chemotaxis term: id: GO:0006935 label: chemotaxis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Class IB phosphoinositide 3-kinase catalytic subunit (p110gamma) activated by C5aR1-released Gbetagamma dimers to synthesize PtdIns(3,4,5)P3 at the leading edge of chemotaxing neutrophils and macrophages. evidence: - source_id: PANTHER:PTN000005674 title: PAINT node PTN000005674 for PIK3CG statement: >- Supports 1-phosphatidylinositol-3-kinase activity (GO:0016303) at the plasma membrane (GO:0005886). - id: rhoa_rhoa_cytoskeletal_switch label: RhoA cytoskeletal switch participant: selector_type: FAMILY family: preferred_term: RhoA cytoskeletal switch family/ortholog group term: id: PANTHER:PTHR24072 label: RHO FAMILY GTPASE representative_members: - preferred_term: RHOA term: id: UniProtKB:P61586 label: 'Transforming protein RhoA (EC 3.6.5.2) (Rho cDNA clone 12) (h12)' ancestral_nodes: - preferred_term: PAINT node PTN000632671 for RHOA term: id: PANTHER:PTN000632671 label: PTN000632671 description: >- Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005886, F:GO:0003924, F:GO:0005525, P:GO:0007015, P:GO:0007165; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000632671 in PTHR24072. evidence: - source_id: PANTHER:PTN000632671 title: PAINT node PTN000632671 for RHOA statement: >- Supports GTPase activity (GO:0003924) and actin cytoskeleton organization (GO:0007015) at the plasma membrane (GO:0005886). function: preferred_term: GTPase activity term: id: GO:0003924 label: GTPase activity processes: - preferred_term: complement component C5a signaling pathway term: id: GO:0038178 label: complement component C5a signaling pathway - preferred_term: chemotaxis term: id: GO:0006935 label: chemotaxis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Small Rho-family GTPase switch that coordinates actomyosin contractility and polarized cell migration downstream of C5aR1 activation. evidence: - source_id: PANTHER:PTN000632671 title: PAINT node PTN000632671 for RHOA statement: >- Supports GTPase activity (GO:0003924) and actin cytoskeleton organization (GO:0007015) at the plasma membrane (GO:0005886). connections: - source: c5a_receptor_engagement target: gi_protein_coupling connection_type: CAUSES description: >- C5a binding stabilizes the active conformation of C5aR1, promoting guanine nucleotide exchange on heterotrimeric Gi. - source: gi_protein_coupling target: c5a_chemotaxis_effector_output connection_type: CAUSES description: >- Released Gbetagamma and Galpha_i-GTP activate PI3Kgamma and Rho-family GTPase effectors to drive myeloid leukocyte chemotaxis.