IL34 (Interleukin-34) Curation Notes

Summary of Gene Function

• Gene symbol: IL34 (UniProtKB:Q6ZMJ4, 242 aa; signal peptide residues 1–20, mature secreted chain residues 21–242).
• Protein family: PANTHER:PTHR28606 (INTERLEUKIN-34, subfamily PANTHER:PTHR28606:SF1 INTERLEUKIN-34).
• Discovery and core mechanism:
• Identified in a functional screen of the human secreted proteome as a homodimeric four-helix-bundle cytokine that binds the macrophage colony-stimulating factor 1 receptor (CSF1R, UniProtKB:P07333) on human monocytes and stimulates monocyte viability [PMID:18467591, "One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor."], as well as CSF1R-dependent ERK1/2 (MAPK1/MAPK3) phosphorylation in human monocytes [Reactome:R-HSA-6787820, "Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008)."].
• Crystal structures of free IL34 and the IL34:CSF1R complex showed that IL34 adopts an antiparallel four-helix bundle fold homologous to CSF1 and binds the N-terminal immunoglobulin domains of CSF1R in an assembly similar to CSF1:CSF1R [PMID:22483114, "Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly."].
• In human peripheral blood monocytes, IL34 signals via CSF1R to drive differentiation into immunosuppressive M2-like (CD14(high) CD163(high) CD1a(-), IL-10(high) IL-12(low)) macrophages [PMID:23409120, "We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) Mφ (IL-34-Mφ). Upon LPS stimulation, IL-34-Mφ exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86."].
• In hepatocellular carcinoma (HCC), IL34 is a direct target of miR-28-5p that mediates tumor-associated macrophage (TAM) infiltration (the cached entry is abstract-only; GOA curators annotated GO:0010759, GO:0043410, GO:0061514, and GO:0120041 from the full text) [PMID:26754294, "Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration."].
• Unlike ubiquitously expressed CSF1, IL34 expression is tissue-restricted—produced predominantly by epidermal keratinocytes and central nervous system neurons—where it is non-redundantly required for the development, survival, and proliferation of Langerhans cells and microglia via CSF1R PMID:30066957. IL34 also interacts with receptor-type protein-tyrosine phosphatase zeta (PTPRZ1) [Reactome:R-HSA-8981657, "It can also bind Receptor-type protein-tyrosine phosphatase zeta (PTPRZ1), a cell surface chondroitin sulfate (CS) proteoglycan."] and syndecan-1 (SDC1), which modulate its bioavailability and signaling [PMID:30066957; Reactome:R-HSA-9009558, "IL34 dimers can bind to the chondroitin sulphate of SDC1. Subsequently, SDC1 modulates IL34-induced CSF1R signaling pathways (Segaliny et al. 2015)."].

Ligand–Receptor Signaling Triage & PAINT Analysis

• Category C gap in GO:0061514 (interleukin-34-mediated signaling pathway):
• In GOA, human IL34 (Q6ZMJ4), mouse Il34 (Q8R1R4), and rat Il34 (Q4KM46) are annotated to GO:0005157 (macrophage colony-stimulating factor receptor binding, IDA PMID:18467591 on Q6ZMJ4, propagated via PAINT PTN002823014 and InterPro IPR020415), which sits under GO:0005102 (signaling receptor binding) rather than GO:0048018 (receptor ligand activity).
• Neither GOA nor PAINT (PANTHER:PTHR28606, node PTN002823014) asserts GO:0005125 (cytokine activity, an is_a child of GO:0048018 receptor ligand activity) on IL34.
• Consequently, even though human IL34 carries GO:0061514 (interleukin-34-mediated signaling pathway, IDA PMID:26754294) and GO:0038145 (macrophage colony-stimulating factor signaling pathway, NAS PMID:30066957), GO:0061514 fails the ligand–receptor signaling check as a Category C gap (binding_only_genes: ["IL34"] / ["Il34"]) across human, mouse, and rat.
• Furthermore, PAINT node PTN002823014 (Euteleostomi, seeded by UniProtKB:Q6ZMJ4) propagates GO:0005576, GO:0005157, GO:0008284, GO:0045651, and GO:0045657, but omits GO:0005125 (cytokine activity) and GO:0061514 (interleukin-34-mediated signaling pathway).
• Resolution:
• In genes/human/IL34/IL34-ai-review.yaml, MODIFY all three GO:0005157 rows (IBA, IDA, IEA) to GO:0005125 (cytokine activity), ACCEPT GO:0061514 (interleukin-34-mediated signaling pathway), and MODIFY GO:0038145 (macrophage colony-stimulating factor signaling pathway, a sibling term of GO:0061514 under GO:0019221 defined by CSF1/M-CSF binding) to GO:0061514.
• In interpro/panther/PTHR28606/PTHR28606-review.yaml, recommend replacing GO:0005157 at PTN002823014 with GO:0005125 (cytokine activity) and adding GO:0061514 (interleukin-34-mediated signaling pathway) at PTN002823014.
• Author modules/il34_signaling.yaml modeling IL34 (PANTHER:PTHR28606) -> CSF1R (PANTHER:PTHR24416:SF47) -> downstream GRB2/PIK3R1/PIK3CA/PLCG2/STAT3/MAPK1/MAPK3 signaling.