Metazoan NLR signaling pathway module

Metazoan nucleotide-binding leucine-rich-repeat receptors detect intracellular perturbations and assemble RIPK-, ASC-, or caspase-containing signaling platforms for inflammatory and antimicrobial responses. Scope is deliberately metazoan; plant NB-LRR receptors share the NB-ARC/LRR architecture but signal through resistosomes rather than through these platforms, and are modelled separately in modules/plant_nlr_resistosome_signaling.yaml.

Curated compact signaling-pathway module generated from verified UniProt exemplar accessions and local PAINT IBD rows. PTN anchors are included only when the exemplar accession appears in an IBD seed row in interpro/panther; roles without local PAINT seeds remain grounded by verified UniProt exemplar accessions. Falcon integration (2026-06-28): Falcon findings are linked as evidence and family-level support. Automatically extracted open-question headings were intentionally not retained as knowledge_gap entries because they were not manually curated. Machine-generated Falcon citations remain curation support and are not manually adjudicated here. Scope clarification (2026-10-06): the title and description now say "metazoan" explicitly. The module's grounding was already metazoan throughout - GO:0035872, NCBITaxon:33208 Metazoa, and NOD2/NLRP3/RIPK2/ASC/ caspase-1 exemplars - but the former title "NLR signaling pathway module" read as pan-taxonomic, which invited plant NB-LRR content that does not belong here. Plant NLRs are now in modules/plant_nlr_resistosome_signaling.yaml. The NLRP3 branch sketched by the nlrp3_inflammasome_sensor, asc_adaptor and caspase-1 annotons here is modelled in full, with structural and GO-CAM grounding, in modules/canonical_nlrp3_inflammasome.yaml; this module keeps those roles as the compact pathway-level view alongside the NOD2-RIPK2 branch. TAK1 step (2026-10-06): the TAK1-TAB complex (MAP3K7 with TAB1 and TAB2/TAB3) was added as the NF-kappaB/MAPK kinase step of the NOD1/NOD2-RIPK2 branch, following the MAP3K7 gene review, the module's deep research and the NOD1/NOD2 GO-CAMs (641ce4dc00000050, 641ce4dc00000214). The earlier "RIPK2 inflammatory signal relay" annoton sat inside the caspase-1 protease output and implied that RIPK2 relays a kinase signal to NF-kappaB. It was removed: RIPK2 is already the NOD adaptor in step 2, and its kinase activity is dispensable for NOD2 signaling (PMID:29452636). Its PAINT anchors remain on the step-2 RIPK2 annoton. The module now branches at the adaptor step: RIPK2 leads to TAK1-TAB (NF-kappaB/MAPK), and ASC leads to caspase-1. TAB1/TAB2/TAB3 are active units of a GO:0097076 complex participant because none has a gene review here. The IKK complex is modeled in MODULE:nfkb_canonical_signaling. CANDIDATE ASSESSED, NOT MODELLED - TRIM25 and EspF (PMID:42711665): a 2026 report screens the mycobacterial ESX-1 effector repertoire, identifies EspF (UniProtKB:P9WJD1, Rv3865) as an activator of the NLRP3 inflammasome that binds the NACHT and LRR domains of NLRP3, and identifies the host E3 ubiquitin ligase TRIM25 (UniProtKB:Q14258) as required for that activation, with TRIM25 binding NLRP3 directly and K63-ubiquitinating it. Neither is added as a part here, for four reasons. (i) EspF is out of scope by taxon. This module declares NCBITaxon:33208 Metazoa, and a secreted bacterial effector is not a metazoan pathway component however strong the evidence; its place in a curated model would be as an exogenous input to a host-pathogen GO-CAM, not as an annoton of the host pathway. (ii) This module already declines, explicitly, to model the E3 ligases that act on its own components. The nlr_adaptor_assembly node states that RIPK2 is ubiquitinated by XIAP (K63-linked) and LUBAC (linear chains) and that "XIAP and LUBAC are not modeled as parts here", even though those chains are the thing that recruits the TAK1-TAB complex that the module does model, and even though the evidence for them is host-intrinsic, replicated and backed by human XIAP deficiency. Adding TRIM25 to the NLRP3 branch on weaker evidence would contradict a convention the file states in its own text. (iii) Evidence scope: every experiment in the report that tests a requirement for TRIM25 is run in an EspF-expressing background - the siRNA knockdown uses doxycycline-inducible EspF THP-1 cells, and both ubiquitination assays co-transfect EspF into wild-type versus TRIM25-knockout HEK293T - so the claim established is that TRIM25 is needed for effector-driven amplification, not that it is a regulator of the uninfected pathway. The one host-intrinsic precedent the authors cite is porcine and proceeds by a different mechanism (enhancing the pro-caspase-1/ASC interaction), and the in vivo arm uses recombinant BCG rather than an EspF-deficient Mtb mutant, a limitation the authors state. (iv) Comparator check: the TRIM-family NLRP3 regulators with stronger and longer-standing support - TRIM31, TRIM50, TRIM62, all named in this paper's own discussion - are absent from this module and from modules/canonical_nlrp3_inflammasome.yaml, and TRIM25 is absent even from modules/rig_i_signaling.yaml, where its best-established function (K63-ubiquitination of the RIG-I CARDs) lies and where GO has curated it into at least five production GO-CAMs. A systematic absence across the modules where the evidence is strongest is a convention, not a gap, and admitting the newest and most context-dependent member first would invert the evidence order. Where this would belong, if the host-intrinsic claim holds up, is a ubiquitin-regulation layer on modules/canonical_nlrp3_inflammasome.yaml, which models the NLRP3 branch in full and currently carries only NEK7 as an optional regulatory part; that module's notes place priming and post-translational regulation deliberately outside its core, so admitting one E3 ligase is a boundary decision for that module rather than something to settle inside a membership handoff, and it would need a genes/human/TRIM25 review first (none exists). No exclusion guard is added: both annotons on the NLRP3 branch are GENE_PRODUCT selectors naming NLRP3 and PYCARD, so no selector here can sweep TRIM25 in and guard text would be redundant. Re-evaluate if TRIM25 loss is shown to blunt canonical NLRP3 activation in human macrophages without a bacterial effector present, or if a TRIM-family regulation layer is built for the canonical module, in which case TRIM31 and TRIM50 should be assessed alongside it rather than after it.