CD14 (human, P08571) review notes

Identity and structure

• Monocyte differentiation antigen CD14; 375 aa precursor, signal peptide 1-19, mature
  membrane form 20-345 with C-terminal propeptide removed on GPI-anchor addition (UniProt).
• No transmembrane or cytoplasmic domain: GPI-anchored.
  PMID:2462937
  PMID:3385210
• Soluble CD14 (sCD14) exists in serum and culture supernatants, by release of the anchored form
  and by secretion of an anchor-less form.
  PMID:2779588
  PMID:3385210
  PMID:25497142
• Crystal structure: bent LRR solenoid with an N-terminal hydrophobic pocket for acyl chains.
  PMID:23264655

Molecular function: lipid-PAMP binding and transfer (carrier)

• CD14 binds LPS monomers (1-2 per CD14), loaded catalytically by LBP.
  PMID:7537731
  PMID:7537731
• CD14 hands LPS on to TLR4-MD2; in vitro reconstitution shows sequential transfer.
  PMID:27986454
  PMID:27986454
• Same carrier logic for triacylated lipopeptides and TLR1/TLR2: sCD14 is not in the final complex.
  PMID:23430250
  PMID:23430250
• Other ligands: LTA PMID:12594207,
  di/triacylated lipopeptides PMID:15294986,
  peptidoglycan PMID:8798531,
  electronegative LDL PMID:23880187,
  apoptotic cells PMID:9548256.
• Summary statement from the structure paper:
  PMID:23264655
• The production GO-CAMs (gocams/index.tsv; 5f46c3b700001031 TLR4 MyD88 pathway and
  5fb9cc0600000727 TLR1-TLR2 triacyl lipopeptide) both model CD14 as GO:0140104 molecular
  carrier activity in extracellular region. This is the MF used as core.

Is CD14 "the receptor"? (project question: which protein performs recognition)

• CD14 is the first host protein to bind LPS at the cell surface, and early work called it the
  LPS receptor PMID:1698311.
• But it has no transmembrane or signalling domain; transmembrane signalling is done by TLR4
  (with MD-2) or TLR2 heterodimers. LPS cross-links to all three proteins of the tripartite complex
  PMID:11274165.
• Conclusion: CD14 does real work in recognition (ligand extraction and delivery; ligand-binding
  pocket), so it is a genuine participant in TLR4 and TLR2 signalling pathways and a member of the
  LPS receptor complex (GO:0046696). It is not itself the signal-transducing LPS immune receptor
  (GO:0001875, whose definition requires transmitting the signal across the membrane). MF best
  captured as LPS binding + molecular carrier activity; GO:0001875 on CD14 MODIFY -> GO:0140104.
• Membrane CD14 has an additional, TLR4-independent signalling role: it drives LPS-induced TLR4
  endocytosis via Syk/PLCgamma2, required for TRIF-dependent IFN output (mouse DCs/macrophages).
  PMID:22078883
  PMID:22078883
  This could justify coreceptor activity (GO:0015026); left as a suggested question rather than
  a new annotation.
• mCD14 required for LPS-induced TLR4/MD-2 dimerization
  PMID:20133493.

In vivo

• Cd14-/- mice resist endotoxic shock and have reduced bacteraemia.
  PMID:8612135

Annotation decisions (summary)

• ACCEPT: LPS binding, LTA binding, molecular carrier activity, TLR4 signalling, cell-surface PRR
  signalling, cellular responses to LPS/LTA/lipopeptides, LPS receptor complex, plasma membrane,
  external side of PM, membrane raft, extracellular region.
• MODIFY: LPS immune receptor activity -> molecular carrier activity; peptidoglycan immune receptor
  activity -> peptidoglycan binding; TLR2/TLR1/TLR6 protein binding -> Toll-like receptor binding;
  generic cell surface receptor signalling -> cell surface PRR signalling; phagocytosis ->
  apoptotic cell clearance.
• REMOVE: apoptotic process (CD14 recognises apoptotic cells, does not execute apoptosis);
  protein binding with FSTL1 and MYO18A (uninformative).
• MARK_AS_OVER_ANNOTATED: opsonin receptor activity (TAS to an LBP paper; CD14 is GPI anchored).
• KEEP_AS_NON_CORE: cytokine-production regulation terms, Golgi, endosome membrane, secretory
  granule membrane, exosome, type I/II IFN production.

Deep research

Falcon deep research status is recorded below once the background job finishes.

Falcon deep research completed (genes/human/CD14/CD14-deep-research-falcon.md) and agrees with
the synthesis above: "The primary molecular function of CD14 is to serve as a co-receptor that
captures, concentrates, and transfers pathogen-associated molecular patterns (PAMPs) and
damage-associated molecular patterns (DAMPs) to downstream signaling receptors". It also reports
(from reviews, not read here as primary papers) CD14 roles in TLR4-independent NFAT signalling,
CD14-dependent cytosolic LPS delivery for the non-canonical (caspase-11/4/5) inflammasome
(Vasudevan 2022, Cell Rep), and flotillin-dependent CD14 trafficking through early endosomes,
recycling endosomes and TGN (Matveichuk 2024). None of these primary papers were cached, so no
NEW annotations were proposed from them.