Complement component C5a signaling pathway module

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.

MODULE:c5a_signalingDRAFTSignaling Pathwaymodules/c5a_signaling.yaml
complement component C5a signaling pathwayGO:0038178
GO:0038178
complement component C5a signaling pathway
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).
PMID:36806352
Mechanism of activation and biased signaling in complement receptor C5aR1.
Establishes C5a binding to C5aR1 and downstream G-protein (Gi) and beta-arrestin signaling.
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.
PMID:37169960
Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins.
Resolves the structural basis of anaphylatoxin C5a recognition and Gi coupling by C5aR1.
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.
PMID:37852260
Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.
Resolves the molecular basis of anaphylatoxin C5a recognition and biased signaling across complement receptors.
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.
PANTHER:PTN002605305
PAINT node PTN002605305 for complement C5
Local PAINT IBD node in PTHR11412 with propagated terms P:GO:0006935, P:GO:0006958; PAINT date 20260729.
PANTHER:PTN000026392
PAINT node PTN000026392 for G protein alpha subunits (GNAI2)
Local PAINT IBD node in PTHR10218 with propagated terms C:GO:0005737, C:GO:0005834, F:GO:0003925, P:GO:0007188; PAINT date 20260828.
PANTHER:PTN000005674
PAINT node PTN000005674 for PIK3CG
Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005886, F:GO:0016303, F:GO:0035005, P:GO:0043491; PAINT date 20240205.
PANTHER:PTN000632671
PAINT node PTN000632671 for RHOA
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.

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).

4Nodes
3Parts
0Variant Sets
0Variants
6Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:c5a_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 9 evidence or coverage gap(s) (12 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
c5_c5a_anaphylatoxin_ligand C5
UniProtKB:P01031
Family Representative 		G protein-coupled receptor binding
GO:0001664 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
c5ar1_c5a_receptor_1 C5AR1
UniProtKB:P21730
Family Representative 		complement receptor activity
GO:0004875 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
c5ar2_c5a_receptor_2 C5AR2
UniProtKB:Q9P296
Family Representative 		complement receptor activity
GO:0004875 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gnai2_gnai2_alpha_subunit GNAI2
UniProtKB:P04899
Family Representative 		G protein activity
GO:0003925 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pik3cg_pi3k_gamma_catalytic_branch PIK3CG
UniProtKB:P48736
Family Representative 		1-phosphatidylinositol-3-kinase activity
GO:0016303 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
rhoa_rhoa_cytoskeletal_switch RHOA
UniProtKB:P61586
Family Representative 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
c5_c5a_anaphylatoxin_ligand Complement C5 subfamily
PANTHER:PTHR11412:SF83
Family 		G protein-coupled receptor binding
GO:0001664 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0001664.
c5ar1_c5a_receptor_1 C5a anaphylatoxin chemotactic receptor 1 subfamily
PANTHER:PTHR24225:SF29
Family 		complement receptor activity
GO:0004875 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24225:SF29.
c5ar2_c5a_receptor_2 C5a anaphylatoxin chemotactic receptor 2 subfamily
PANTHER:PTHR24225:SF1
Family 		complement receptor activity
GO:0004875 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24225:SF1.
gnai2_gnai2_alpha_subunit Guanine nucleotide-binding protein G(i) subunit alpha-2 subfamily
PANTHER:PTHR10218:SF73
Family 		G protein activity
GO:0003925 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10218:SF73.
pik3cg_pi3k_gamma_catalytic_branch PI3K gamma catalytic branch family/ortholog group
PANTHER:PTHR10048
Family 		1-phosphatidylinositol-3-kinase activity
GO:0016303 		Family Scope Restricted
GO:0016303 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. All three PI3K classes phosphorylate phosphatidylinositol at the 3-position: class III VPS34 (SF7, selected by the phosphoinositide_biosynthesis and phagosome_maturation modules, and its sole activity), the class II PI3Ks (SF28, SF29, SF30), and the class I catalytic subunits in vitro (SF107, SF33, SF34, SF35), whose PIK3CA and PIK3CD reviews keep the term. Not the type III PI4Ks. SF111 (C. elegans AGE-1, a class I catalytic subunit) is listed too; its review keeps the in vitro activity as non-core. For the class I subfamilies the scope records a measured in vitro activity, not the physiological one: in cells their main substrate is PI(4,5)P2. Read "safe" for those subfamilies with that caveat.
rhoa_rhoa_cytoskeletal_switch RhoA cytoskeletal switch family/ortholog group
PANTHER:PTHR24072
Family 		GTPase activity
GO:0003924 		Family Function Unreviewed
Family review leaves GO:0003924 UNRESOLVED. Full-length RHOJ is directly demonstrated to hydrolyze GTP, so RHOJ must not be labelled GTPase-deficient simply by analogy to atypical Rnd proteins. The benchmark product has a disrupted distal sequence and cannot inherit intact RHOJ kinetics. Across the broader family, nucleotide regulation and catalytic competence require branch- and product-specific evidence.

Gene-review completeness (4/6 grounded genes reviewed)

3 complete review(s) · 0 with deep research · 2 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
C5 P01031 ✓ ✓ ✗
GNAI2 P04899 ✓ ✓ ✗
C5AR1 P21730 ✗ — —
PIK3CG P48736 ✓ 99/102 ✗
C5AR2 Q9P296 ✗ — —
RHOA P61586 ✓ ✓ ✗

Details

Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829
Complement component C5a signaling pathwaySignaling Pathwayc5a_signaling
complement component C5a signaling pathwayGO:0038178
Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829

Connections

C5a binding stabilizes the active conformation of C5aR1, promoting guanine nucleotide exchange on heterotrimeric Gi.
Released Gbetagamma and Galpha_i-GTP activate PI3Kgamma and Rho-family GTPase effectors to drive myeloid leukocyte chemotaxis.
Part 1: C5a ligand-receptor engagement
C5a anaphylatoxin receptor engagementRegulatory Stepc5a_receptor_engagement

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

C5 (C5a anaphylatoxin) ligand
c5_c5a_anaphylatoxin_ligand
Participant: Family: Complement C5 subfamily
Family:
Complement C5 subfamilyPANTHER:PTHR11412:SF83
Representative Members: C5UniProtKB:P01031

Function

G protein-coupled receptor bindingGO:0001664

Processes

complement component C5a signaling pathwayGO:0038178 cell chemotaxisGO:0060326

Locations

extracellular regionGO:0005576

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.

PMID:36806352
Mechanism of activation and biased signaling in complement receptor C5aR1.
Demonstrates C5a binding and activation of C5aR1 to initiate downstream G-protein and beta-arrestin signaling.
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.
C5AR1 complement C5a receptor 1
c5ar1_c5a_receptor_1
Participant: Family: C5a anaphylatoxin chemotactic receptor 1 subfamily
Family:
C5a anaphylatoxin chemotactic receptor 1 subfamilyPANTHER:PTHR24225:SF29
Representative Members: C5AR1UniProtKB:P21730

Function

complement receptor activityGO:0004875

Processes

complement component C5a signaling pathwayGO:0038178 chemotaxisGO:0006935

Locations

plasma membraneGO:0005886

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.

PMID:37169960
Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins.
Resolves C5a-bound C5aR1 in complex with heterotrimeric Gi.
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.
C5AR2 complement C5a receptor 2
c5ar2_c5a_receptor_2
Participant: Family: C5a anaphylatoxin chemotactic receptor 2 subfamily
Family:
C5a anaphylatoxin chemotactic receptor 2 subfamilyPANTHER:PTHR24225:SF1
Representative Members: C5AR2UniProtKB:Q9P296

Function

complement receptor activityGO:0004875

Processes

complement component C5a signaling pathwayGO:0038178

Locations

plasma membraneGO:0005886

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.

PMID:36806352
Mechanism of activation and biased signaling in complement receptor C5aR1.
Supports C5a receptor engagement and beta-arrestin pathway activation.
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.
Part 2: heterotrimeric g protein coupling
Gi protein couplingRegulatory Stepgi_protein_coupling

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

GNAI2 alpha subunit
gnai2_gnai2_alpha_subunit
Participant: Family: Guanine nucleotide-binding protein G(i) subunit alpha-2 subfamily
Family:
Guanine nucleotide-binding protein G(i) subunit alpha-2 subfamilyPANTHER:PTHR10218:SF73
Representative Members: GNAI2UniProtKB:P04899

Function

G protein activityGO:0003925

Processes

complement component C5a signaling pathwayGO:0038178

Locations

plasma membraneGO:0005886

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.

PMID:36806352
Mechanism of activation and biased signaling in complement receptor C5aR1.
Resolves direct coupling of C5a-activated C5aR1 to heterotrimeric Gi.
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.
Part 3: C5a chemotaxis effector output
C5a chemotaxis and effector outputRegulatory Stepc5a_chemotaxis_effector_output

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

PI3K gamma catalytic branch
pik3cg_pi3k_gamma_catalytic_branch
Participant: Family: PI3K gamma catalytic branch family/ortholog group
Family:
PI3K gamma catalytic branch family/ortholog groupPANTHER:PTHR10048
Representative Members: PIK3CGUniProtKB:P48736

Function

1-phosphatidylinositol-3-kinase activityGO:0016303

Processes

complement component C5a signaling pathwayGO:0038178 chemotaxisGO:0006935

Locations

plasma membraneGO:0005886 cytosolGO:0005829

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.

PANTHER:PTN000005674
PAINT node PTN000005674 for PIK3CG
Supports 1-phosphatidylinositol-3-kinase activity (GO:0016303) at the plasma membrane (GO:0005886).
RhoA cytoskeletal switch
rhoa_rhoa_cytoskeletal_switch
Participant: Family: RhoA cytoskeletal switch family/ortholog group
Family:
RhoA cytoskeletal switch family/ortholog groupPANTHER:PTHR24072
Representative Members: RHOAUniProtKB:P61586

Function

GTPase activityGO:0003924

Processes

complement component C5a signaling pathwayGO:0038178 chemotaxisGO:0006935

Locations

plasma membraneGO:0005886 cytosolGO:0005829

Small Rho-family GTPase switch that coordinates actomyosin contractility and polarized cell migration downstream of C5aR1 activation.

PANTHER:PTN000632671
PAINT node PTN000632671 for RHOA
Supports GTPase activity (GO:0003924) and actin cytoskeleton organization (GO:0007015) at the plasma membrane (GO:0005886).