A7RHZ4 (Nematostella vectensis MyD88, NvMyD88) review notes

Status of inputs

• Review originally done from UniProt, GOA and cached literature; Falcon deep research arrived
  later and was cross-checked (see the section at the end).
• UniProt A7RHZ4 (TrEMBL, PE 4 predicted, 245 aa, flagged Fragment with NON_TER at residue 1):
  Death domain 1-65 (PROSITE PS50017), TIR domain 104-236 (PS50104). InterPro IPR017281 (MyD88 family),
  PANTHER PTHR15079:SF3 (MYD88). ORF NEMVEDRAFT_v1g82163. Name from ProtNLM. The N-terminus is missing,
  so the death domain is probably incomplete at its start.
• All 5 GOA rows are IEA (4 InterPro2GO, 1 UniProt SubCell). No experimental annotation and, as far as
  I could find in PubMed, no functional study of the Nematostella MyD88 protein itself.

What is known

• Nematostella has a single MyD88 homologue and a single TLR PMID:17437634;
  confirmed across actiniarians PMID:27806695.
  MyD88 in these surveys is defined by death domain + TIR architecture
  PMID:27806695.
• Nematostella also has IL-1R-like TIR proteins, which form a clade distinct from vertebrate IL-1Rs
  PMID:17437634.
  There is no IL-1 cytokine in cnidarians to my knowledge (not sourced; not used for any annotation), so
  IL-1-mediated signalling terms should not transfer.
• The Nv-TLR TIR domain binds human MYD88 and MAL, and Nv-TLR activates NEMO-dependent NF-kappaB in
  HEK293 cells, responding to heat-killed Vibrio coralliilyticus and flagellin
  PMID:29109290,
  PMID:29109290.
  This is evidence about the receptor with human adaptors; NvMyD88 itself was not tested.
• Coral (Orbicella) TLR TIR binds human MYD88 PMID:29080785.
• Hydra MyD88 knockdown: role in bacterial colonisation and defence against Pseudomonas - the only
  in vivo cnidarian MyD88 loss-of-function evidence
  PMID:23112184.
• Nv-NF-kappaB is p50/p52-like, lacks C-terminal IkappaB-like repeats; separate IkappaB genes exist
  PMID:17120026.
  Nematostella NF-kappaB linked to immunity (starvation reduces NF-kappaB and increases P. aeruginosa
  susceptibility, PMID:37420095).

Decisions

• GO:0070976 TIR domain binding (IEA): ACCEPT - core adaptor MF; homotypic TIR binding is the defining
  MyD88 activity; cnidarian TLR TIRs bind (human) MyD88.
• GO:0002755 MyD88-dependent TLR signaling pathway (IEA): ACCEPT - Nematostella has one TLR; Nv-TLR can
  respond to bacterial products and signal via MyD88 in a reconstituted system; Hydra MyD88 needed for
  bacterial sensing. The definition's "directly bind pattern motifs" clause is not shown for Nv-TLR, but
  the reconstitution data (flagellin, Vibrio) are consistent. Accept as an inference.
• GO:0043123 positive regulation of canonical NF-kappaB signal transduction (IEA): ACCEPT with caveat -
  Nematostella has separate NF-kappaB and IkappaB proteins and IKK homologues; Nv-TLR drives NEMO-dependent
  NF-kappaB activation in human cells. Not directly shown for NvMyD88.
• GO:0007165 signal transduction (IEA): ACCEPT (broad, correct).
• GO:0005737 cytoplasm (IEA): ACCEPT - no TM or signal peptide; MyD88 family is cytosolic.
• Not transferred: GO:0070498 interleukin-1-mediated signaling pathway and numbered TLR terms
  (e.g. GO:0034142 TLR4) - no IL-1 ligand, and no evidence of TLR4-type ligand specificity for Nv-TLR
  (TIR similarity to TLR4 does not imply LPS recognition).
• No NEW annotations: nothing experimental on this protein.

Deep-research cross-check (2026-09-30)

Compared A7RHZ4-deep-research-falcon.md with the review.
- Agrees: MyD88-family DD + TIR adaptor, fragmentary record, cytoplasmic, non-enzymatic; Nv-TLR TIR
binds human MYD88/MAL; reconstituted Nv-TLR responds to flagellin and heat-killed Vibrio; Hydra MyD88
loss-of-function; no direct experiment on A7RHZ4 itself. Most mechanistic detail in the report
(Myddosome stoichiometry, intermediate domain, IRAK/TRAF6/TAK1) is mammalian and was not transferred.
- Added (verified in PMID:29109290 full text): "mRNAs for homologs of all predicted TLR–to–NF-κB pathway
proteins were detected in nematosomes" - one sentence in the description and a core-function
supported_by. Nv-TLR morpholino knockdown affects early development, proposed to be NF-kappaB
independent - added as a suggested question on whether NvMyD88 mediates it.
- No annotation actions changed.