id: P22287 gene_symbol: AVR9 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:5499 label: Fulvia fulva description: >- AVR9 (race-specific elicitor A9) is a small secreted cysteine-rich effector of the biotrophic tomato leaf mould fungus Fulvia fulva (syn. Cladosporium fulvum). The 63-residue precursor carries an N-terminal signal peptide; after secretion the proprotein is trimmed by fungal and host proteases into a stable 28-residue mature peptide that accumulates in the apoplast of infected tomato leaves, where the fungus grows between mesophyll cells. The mature peptide is a three-stranded antiparallel beta-sheet held together by three disulfide bonds arranged as a cystine knot (knottin), with a fold resembling carboxypeptidase inhibitors; however, no protease-inhibitory or other biochemical activity has been demonstrated, and the intrinsic contribution of AVR9 to fungal virulence is unknown. AVR9 is best known as an avirulence determinant: in tomato carrying the receptor-like protein Cf-9 it triggers a hypersensitive response (localized necrosis, oxidative burst and defence activation) and resistance, in accordance with the gene-for-gene model. Recognition appears to be indirect; radiolabelled AVR9 binds a high-affinity plasma-membrane site present in tomato with or without Cf-9 and in other solanaceous plants, and binding affinity of mutant peptides correlates with their necrosis-inducing activity. Avr9 expression is strongly induced in planta and under nitrogen limitation through the nitrogen regulator NRF1. Field races that overcome Cf-9 resistance typically lack the entire subtelomeric Avr9 gene. alternative_records: - id: L7YER9 relationship: REFERENCE_PROTEOME_EQUIVALENT reference_proteome: UP000756132 reviewed_on: '2026-10-19' reason: Retain P22287 as the primary Swiss-Prot accession. The reference Avr9 precursor is exactly identical across all 63 residues and is the sole significant hit. This supports equivalent protein representation. Retain the reviewed race-5 accession and its evidence rather than transferring race-specific claims automatically. evidence: - type: PROTEOME_SEARCH description: MMseqs2 searched 14,687 sequences across UP000756132 at E <= 1e-5 and sensitivity 7.5, returning 1 hits. Every returned sequence was globally aligned using BLOSUM62 with gap-open -10 and extension -0.5. Scores and sequences for all 1 returned candidates are retained, with 1 detailed alignment files. The heuristic search does not establish genomic absence or unique locus identity. supported_by: - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: 'target_sequence_count: 14687' - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: 'candidate_count: 1' - type: SEQUENCE_COMPARISON description: 'L7YER9: 63 identities across 63 global-alignment columns (100.0% identity including gaps), 0 substitutions and 0 gap columns. Query coverage is 100.0%; target coverage is 100.0%. Sequence similarity is interpreted in the manual rationale. Identity over paired residues is 100.0000% (63/63); gap columns are excluded from this denominator.' supported_by: - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: |- query_length: 63 target_length: 63 alignment_columns: 63 identities: 63 mismatches: 0 gap_columns: 0 identity_percent: 100.0 query_coverage_percent: 100.0 target_coverage_percent: 100.0 - type: PROTEOME_MEMBERSHIP description: The primary accession is outside every searched exact-taxon reference proteome. Current UniProt records place L7YER9 in UP000756132 and give it the same taxon as the primary. supported_by: - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: 'primary_in_any_reference_proteome: false' - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: 'alternative_in_reference_proteome: true' - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: 'same_taxon: true' - type: RECORD_HISTORY description: 'Sampled UniSave observations: 01-OCT-2014, entry version 50.: no Proteomes cross-reference; 02-DEC-2020, entry version 58.: no Proteomes cross-reference; 25-MAY-2022, entry version 60.: no Proteomes cross-reference. These dated observations do not establish uninterrupted membership/absence, the exact change date, or UniProt''s motivation.' supported_by: - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: |- entry_date: 01-OCT-2014, entry version 50. proteomes: [] - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: |- entry_date: 02-DEC-2020, entry version 58. proteomes: [] - reference_id: file:FULFL/AVR9/AVR9-record-evidence.yaml supporting_text: |- entry_date: 25-MAY-2022, entry version 60. proteomes: [] existing_annotations: - term: id: GO:0080185 label: effector-mediated activation of plant hypersensitive response by symbiont evidence_type: EXP original_reference_id: PMID:10998185 qualifier: involved_in review: summary: >- Lauge et al. tested tomato lines and Lycopersicon accessions by injection of purified C. fulvum proteins and found HR-associated recognition of AVR9 (alongside AVR4 and other secreted proteins) in multiple Lycopersicon species. AVR9-triggered, Cf-9-dependent HR is the single best-established biological activity of this peptide. action: ACCEPT reason: >- The GO:0080185 definition explicitly covers the direct or indirect recognition of a symbiont effector by plant resistance proteins leading to HR, which is exactly what AVR9 does in Cf-9 plants. In GO the effector that is recognised is treated as a participant in this symbiont process (analogous to a ligand participating in the signalling it triggers), and the same term is used for other recognised fungal avirulence effectors. Abstract-only access, but the abstract explicitly reports HR-associated recognition of AVR9, and the curator has read the full text. Note: in the current ontology GO:0080185 is_a GO:0034055, whose definition says the host cell death is activated "to suppress the host innate immune response"; that inherited implication does not fit an avirulence factor whose recognition confers resistance (see suggested_questions). supported_by: - reference_id: PMID:10998185 supporting_text: Host resistance is based on specific recognition of extracellular fungal proteins, resulting in a hypersensitive response (HR). - reference_id: PMID:10998185 supporting_text: in addition to recognition of the race-specific elicitors AVR4 and AVR9 of C. fulvum, occurs among Lycopersicon species - term: id: GO:0080185 label: effector-mediated activation of plant hypersensitive response by symbiont evidence_type: EXP original_reference_id: PMID:16167771 qualifier: involved_in review: summary: >- Kruijt et al. identified AVR9-responsive plants throughout the genus Lycopersicon and, by agroinfiltration, Hcr9 homologues (Hcr9-Avr9s) highly identical to Cf-9 that mediate AVR9 recognition. action: ACCEPT reason: >- Experimental demonstration that AVR9 elicits Cf-9/Hcr9-dependent responses in diverse wild tomato species; consistent with the core, well-established role of AVR9 as the elicitor of Cf-9-mediated HR. Abstract-only; deferring to the curator on assay details. supported_by: - reference_id: PMID:16167771 supporting_text: confer resistance to strains of the leaf mold fungus Cladosporium fulvum that secrete the Avr4 and Avr9 elicitor proteins, respectively - reference_id: PMID:16167771 supporting_text: Plants responsive to the Avr4 and Avr9 elicitor proteins were identified throughout the genus Lycopersicon. - term: id: GO:0140404 label: effector-mediated perturbation of host innate immune response by symbiont evidence_type: EXP original_reference_id: PMID:26946045 qualifier: involved_in review: summary: >- This paper characterises Ve1 homologues and Ave1 recognition from Verticillium dahliae; AVR9 is not mentioned in the cached abstract and was presumably used in the full text as the Cf-9/Avr9 HR control in transient assays. The general claim that AVR9 modulates (here, activates) host innate immunity is correct. action: MODIFY reason: >- Full text not available to this review, so the specific assay cannot be verified; the experimental claim is not disputed and is not removed. The broad term (modulation, either activation or suppression, of host innate immunity) is correct for AVR9, but the only immune-modulating activity ever documented for AVR9 is elicitation of Cf-9-dependent HR, so the informative term is GO:0080185 (already carried with experimental support). Refining avoids implying an immunosuppressive activity, which the perturbation subtree mostly describes and which AVR9 is not known to have. proposed_replacement_terms: - id: GO:0080185 label: effector-mediated activation of plant hypersensitive response by symbiont supported_by: - reference_id: PMID:26946045 supporting_text: plants use immune receptors to try and intercept such effectors in order to prevent pathogen colonization - reference_id: PMID:10998185 supporting_text: in addition to recognition of the race-specific elicitors AVR4 and AVR9 of C. fulvum, occurs among Lycopersicon species - term: id: GO:0140404 label: effector-mediated perturbation of host innate immune response by symbiont evidence_type: TAS original_reference_id: PMID:25902074 qualifier: involved_in review: summary: >- Iida et al. (full text) survey Avr genes in Japanese C. fulvum isolates; the introduction states that AVR9 triggers HR in Cf-9 plants, and all isolates overcoming Cf-9 lacked the entire Avr9 gene. The paper also states that the biological function of AVR9 is unknown. action: MODIFY reason: >- The statement traceable to this paper is specifically that AVR9 triggers a hypersensitive response in Cf-9 plants, which is captured precisely by GO:0080185. The broad "perturbation" parent adds nothing and, because its subtree is dominated by suppression terms, is easily misread as implying an immunosuppressive virulence activity that has never been shown for AVR9. proposed_replacement_terms: - id: GO:0080185 label: effector-mediated activation of plant hypersensitive response by symbiont supported_by: - reference_id: PMID:25902074 supporting_text: their encoded proteins trigger a hypersensitive response (HR) in host plants carrying the corresponding Cf-2, Cf-4, Cf-4E, Cf-5, and Cf-9 genes, respectively - reference_id: PMID:25902074 supporting_text: Although the biological function of the Avr9 protein is not known - term: id: GO:0140404 label: effector-mediated perturbation of host innate immune response by symbiont evidence_type: TAS original_reference_id: PMID:9437864 qualifier: involved_in review: summary: >- Thomas et al. clone Cf-4 and compare it with Cf-9; the paper states that Cf-9 confers resistance through recognition of AVR9. AVR9 itself is not studied experimentally. action: MODIFY reason: >- The traceable statement is that AVR9 is the avirulence determinant recognised by Cf-9 to give resistance, i.e. Cf-9-dependent activation of host immunity/HR. GO:0080185 captures this more precisely than the broad perturbation parent. proposed_replacement_terms: - id: GO:0080185 label: effector-mediated activation of plant hypersensitive response by symbiont supported_by: - reference_id: PMID:9437864 supporting_text: confer resistance to Cladosporium fulvum through recognition of different avirulence determinants (AVR4 and AVR9) - term: id: GO:0140593 label: host apoplast evidence_type: IDA original_reference_id: PMID:8208859 review: summary: >- Mature 28-residue AVR9 accumulates in infected tomato leaves and was originally purified from apoplastic fluid of infected tomato; plant factors complete its processing. The apoplast is where AVR9 is perceived. action: NEW reason: >- Location annotation, so the process participation test does not apply. GOA has no cellular component annotation for AVR9 even though its apoplastic localization is its defining feature; host apoplast (GO:0140593) is the term used for other apoplastic fungal effectors (e.g. Mg1LysM, Mg3LysM, AvrLm1) in GOA. supported_by: - reference_id: PMID:8208859 supporting_text: the elicitor accumulates in infected leaves as a 28-amino acid (aa) peptide - reference_id: PMID:8208859 supporting_text: We demonstrated that plant factors process the 34-aa peptide into the mature 28-aa peptide. - reference_id: PMID:8555455 supporting_text: The amino acid sequence of the processed AVR9 peptide present in apoplastic fluid (AF) of pAVIR1 transformed plants - reference_id: file:FULFL/AVR9/AVR9-deep-research-falcon.md supporting_text: 28-residue mature elicitor recovered from infected tomato-leaf references: - id: file:FULFL/AVR9/AVR9-record-evidence.yaml title: Compact archived record and sequence evidence for P22287 - id: PMID:10998185 title: Specific HR-associated recognition of secreted proteins from Cladosporium fulvum occurs in both host and non-host plants. findings: [] - id: PMID:16167771 title: The Cf-4 and Cf-9 resistance genes against Cladosporium fulvum are conserved in wild tomato species. findings: [] - id: PMID:25902074 title: Novel Mutations Detected in Avirulence Genes Overcoming Tomato Cf Resistance Genes in Isolates of a Japanese Population of Cladosporium fulvum. findings: [] - id: PMID:26946045 title: Broad taxonomic characterization of Verticillium wilt resistance genes reveals an ancient origin of the tomato Ve1 immune receptor. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Abstract (cached) is about Ve1/Ave1 and does not mention AVR9; AVR9 presumably appears in the full text as a Cf-9/Avr9 control. Not verified. - id: PMID:9437864 title: Characterization of the tomato Cf-4 gene for resistance to Cladosporium fulvum identifies sequences that determine recognitional specificity in Cf-4 and Cf-9. findings: [] - id: PMID:8208859 title: The AVR9 race-specific elicitor of Cladosporium fulvum is processed by endogenous and plant proteases. - id: PMID:9119054 title: 'The race-specific elicitor AVR9 of the tomato pathogen Cladosporium fulvum: a cystine knot protein. Sequence-specific 1H NMR assignments, secondary structure and global fold of the protein.' - id: PMID:12239406 title: A High-Affinity Binding Site for the AVR9 Peptide Elicitor of Cladosporium fulvum Is Present on Plasma Membranes of Tomato and Other Solanaceous Plants. - id: PMID:9625714 title: Correlation between binding affinity and necrosis-inducing activity of mutant AVR9 peptide elicitors. - id: PMID:11277429 title: Expression of the Avirulence gene Avr9 of the fungal tomato pathogen Cladosporium fulvum is regulated by the global nitrogen response factor NRF1. - id: PMID:8555455 title: Production of the AVR9 elicitor from the fungal pathogen Cladosporium fulvum in transgenic tobacco and tomato plants. - id: file:FULFL/AVR9/AVR9-deep-research-falcon.md title: Deep research report on Fulvia fulva AVR9 (Falcon) core_functions: - description: >- Secreted, protease-matured cystine-knot peptide that accumulates in the tomato leaf apoplast, where it is perceived (apparently indirectly, via a high-affinity plasma-membrane binding site) by the Cf-9 receptor-like protein system, triggering a hypersensitive response and resistance in Cf-9 plants. No molecular function is asserted: no biochemical activity has been demonstrated (carboxypeptidase-inhibitor-like fold only), direct binding to Cf-9 has not been shown, and the intrinsic virulence role is unknown. directly_involved_in: - id: GO:0080185 label: effector-mediated activation of plant hypersensitive response by symbiont locations: - id: GO:0140593 label: host apoplast supported_by: - reference_id: PMID:8208859 supporting_text: encodes a race-specific peptide elicitor that induces a hypersensitive response in tomato plants carrying the complementary resistance gene Cf9 - reference_id: PMID:12239406 supporting_text: Binding kinetics and binding capacity were similar for membranes of the MM-Cf0 and MM-Cf9 genotypes. - reference_id: PMID:9625714 supporting_text: a positive correlation between their affinity to the membrane-localized binding site and their necrosis-inducing activity in MoneyMaker-Cf9 tomato was found - reference_id: PMID:9119054 supporting_text: The AVR9 protein reveals the presence of a cystine knot suggested_questions: - question: >- GO:0080185 (effector-mediated activation of plant HR by symbiont) is_a GO:0034055, whose definition states that host cell death is activated "to suppress the host innate immune response", which in turn is_a GO:0140403 (effector-mediated suppression of host innate immune response). For avirulence effectors such as AVR9, recognition of which activates immunity and confers resistance, this inherits a false suppression claim. Should GO:0080185 be re-parented (e.g. directly under GO:0140404 perturbation of host innate immune response) or GO:0034055 be redefined? - question: >- GO represents "being recognised by a host immune receptor" only through the process term GO:0080185, with no molecular function. Is the effector legitimately a participant (ligand-like) in this process, and should there be a molecular function or relation for an elicitor that is perceived indirectly (no demonstrated binding to its cognate receptor)? - question: >- What is the identity of the high-affinity AVR9 binding site present in plasma membranes of Cf-9 and Cf-0 tomato and other Solanaceae, and is it the virulence target guarded by Cf-9? - question: >- Does AVR9 have any intrinsic virulence function on susceptible (Cf-0) tomato, given its carboxypeptidase-inhibitor-like fold and the frequent deletion of Avr9 in field races? suggested_experiments: - description: >- Compare fitness and colonisation of isogenic Avr9 deletion and complemented strains on Cf-0 tomato, including competition assays, to test for an intrinsic virulence contribution. - description: >- Affinity purification / crosslinking of labelled AVR9 to tomato plasma membranes from Cf-0 and Cf-9 plants to identify the high-affinity binding protein, followed by tests of whether it associates with Cf-9/SOBIR1. - description: >- Screen AVR9 against a panel of tomato apoplastic proteases and other candidate targets suggested by the knottin fold to identify a biochemical activity.