PIGU (Q9H490) review notes

Summary of verified biology

PIGU (GPI-anchor transamidase component PIG-U; CDC91L1) is one of five subunits of the
glycosylphosphatidylinositol (GPI) transamidase (GPI-T) complex — PIGK, GPAA1, PIGT, PIGS, PIGU.
GPI-T is an ER-membrane complex that removes the C-terminal GPI-attachment signal peptide of
proprotein substrates and covalently attaches a pre-assembled GPI anchor to the newly exposed
C-terminus (the ω-site) in the ER lumen. PIGK is the catalytic (cysteine-protease/legumain-like)
subunit; GPAA1 is proposed to form the amide bond. PIGU is a non-catalytic accessory subunit:
it is a multi-pass ER membrane protein that binds the lipid portion of the GPI substrate and is
thought to help recognise/present the lipid GPI and to organise the transmembrane layer of the
complex (recruiting other subunits). Cells lacking PIGU still assemble the other four subunits but
have no transamidase activity.

Key provenance

• Five-subunit complex, ER, PIGU = fifth subunit; class-U mutant cells accumulate GPI, lack in-vitro
  transamidase activity, and lose ability to cleave the GPI attachment signal peptide
  PMID:12802054;
  PMID:12802054.
• GPI-T is ER-membrane, replaces C-terminal GPI attachment signal with pre-assembled GPI
  PMID:11483512.
• Five subunits, PIGK catalytic, PIGU recognises lipid portion of GPI, loss of PIGU abolishes activity
  PMID:34576938;
  PMID:34576938.
• Cryo-EM structure of five-subunit human GPI-T; PIGK catalytic; TM cleft = GPI substrate-binding site
  PMID:35165458.
• Equimolar heteropentamer, ER-membrane GPI-T conserved among eukaryotes
  PMID:35551457;
  PMID:35551457.
• Liganded GPI-T structures; GPI binds GPI-T; PIGU is one of the five subunits contacting GPI
  PMID:37684232.
• Disease: biallelic PIGU variants cause NEDBSS / inherited GPI-anchor deficiency (GPIBD) with
  developmental delay, intellectual disability, epilepsy, brain anomalies
  PMID:31353022.

Annotation decisions (high-level)

• Core: BP = GPI anchor biosynthetic process (GO:0006506) / attachment of GPI anchor to protein
  (GO:0016255); CC = ER membrane (GO:0005789) + GPI-anchor transamidase complex (GO:0042765).
• MF: GOA carries NO catalytic MF for PIGU. The only MF terms are protein binding (GO:0005515, IPI,
  HuRI high-throughput — mark over-annotated) and GPI anchor binding (GO:0034235, IDA/IMP —
  accept as a subunit-level binding activity, PIGU binds the lipid portion of GPI). Note: UniProt DR
  block lists an IBA GPI-anchor transamidase activity (GO:0003923) but it is NOT in the GOA TSV, so
  it is not reviewed here and NOT invented as a core function (PIGU is non-catalytic).
• plasma membrane (GO:0005886, IDA, PMID:15034568) and regulation of receptor signaling pathway via JAK-STAT (GO:0046425, IDA, PMID:15034568): from the bladder-cancer oncogene paper. These are
  downstream/indirect consequences of PIGU overexpression (uPAR up, STAT3 phosphorylation), not the
  core ER-lumenal biosynthetic function. PIGU itself is an ER-membrane protein, not a PM protein;
  the paper reports overexpression effects. Mark over-annotated / non-core rather than core.
• membrane (GO:0016020) IEA/HDA: correct but non-informative parent of ER membrane; keep as
  non-core.