SPINK5 (Q9NQ38) notes

2026-10-21 — Full re-review, independent of the ProtNLM2 predictions

Context: SPINK5 was reviewed as the closest experimentally characterised relative of fly CG32354 (Q9VSK1).
No ProtNLM2 output was consulted.

Deep research

just deep-research-falcon human SPINK5 --fallback perplexity-lite failed: Edison (falcon) returned
403 Forbidden at authentication, and the perplexity-lite fallback timed out after 600 s. No deep-research
file exists. The review rests on the cached primary literature listed below (mostly abstract-only;
PMID:17596512 and PMID:19414552 have full text).

Evolutionary grounding

• PANTHER 19.0: PTHR10913 (FOLLISTATIN-RELATED), subfamily SF71 "SERINE PROTEASE INHIBITOR KAZAL-TYPE 5".
  UniProt still cross-references the older PTHR47499:SF1.
• Tree analysis (SPINK5-bioinformatics/panther_tree.py, RESULTS.md): the serine-type endopeptidase
  inhibitor IBD node PTN000099251 (Theria) covers only 12 therian SPINK5 orthologs. Mouse Spink5 (Q148R4)
  is inside it, so mouse findings transfer. TMEFF2 diverges at the Euteleostomi duplication; fly CG32354 and
  Fs share only the Bilateria speciation node PTN000857333.
• Implication for transfer to fly: the inhibitor activity should not be projected to Q9VSK1. PAINT placed
  the IBD at Theria deliberately.

Function (experimental, human protein unless stated)

• Trypsin inhibition by native domain HF7665 PMID:10419450
• Full-length recombinant LEKTI inhibits plasmin, subtilisin A, cathepsin G, elastase and trypsin, but not
  chymotrypsin or cysteine proteinases PMID:12667078
• Domain 6 inhibits KLK5 and KLK7 PMID:16307658
• Furin fragments inhibit KLK5, KLK7 and KLK14; pH-dependent release of KLK5
  PMID:17596512
• Caspase 14 inhibition in vitro, single study PMID:20533828; not used for GO.
• Localization: lamellar granules, then extracellular space of the stratum granulosum PMID:15675955.
• Mouse genetics: Spink5-null mice show DSG1 degradation and barrier loss PMID:15619623, increased
  profilaggrin processing PMID:15590704, KLK5-PAR2-TSLP inflammation PMID:19414552, and increased
  cathelicidin antimicrobial activity PMID:17012259.

Decisions in brief

• Core MF: GO:0004867 (ACCEPT IBA + two IDA). GO:0030414 MODIFY to GO:0004867.
• Extracellular region rows MODIFY to extracellular space (GO:0005615). Lamellar body ACCEPT.
• Differentiation terms (epidermal, epithelial, IBA cell differentiation) MARK_AS_OVER_ANNOTATED: the
  evidence is that LEKTI is a differentiation marker, or the phenotype is downstream of protease
  hyperactivity.
• REMOVE: negative regulation of angiogenesis (no evidence), hair cell differentiation (sensory hair cell
  term; Netherton hair defect is a hair shaft defect).
• Cytosol IDA is from a signal-peptide-deleted mutant, so MARK_AS_OVER_ANNOTATED.
• No NEW terms. Desquamation and skin barrier are processes that LEKTI regulates rather than performs, and
  GO has no "regulation of corneocyte desquamation" term; this is raised as a question in the review.