PNPLA2 (ATGL) review notes

UniProt Q96AD5 (PLPL2_HUMAN), HGNC:30802. The literature synthesis below was done manually
from the cached publications and the UniProt record while falcon deep research was running
(the client reported a timeout, but PNPLA2-deep-research-falcon.md was written afterwards).
The falcon report agrees with this review: lipid-droplet TAG hydrolysis is the primary
function, ABHD5 co-activates and G0S2 inhibits ATGL, and PLA2, transacylase and PEDF-R
activities are context-specific; it also reports negligible retinyl-ester hydrolysis by ATGL,
consistent with keeping the retinyl esterase annotations as non-core.

Core biology

• PNPLA2/ATGL (adipose triglyceride lipase, desnutrin, iPLA2-zeta, TTS-2.2, PEDF-R) is a
  patatin-domain serine hydrolase that catalyzes the first, rate-limiting step of
  intracellular triacylglycerol (TAG) hydrolysis on cytoplasmic lipid droplets, producing
  diacylglycerol (DAG) plus a fatty acid
  PMID:15550674.
• High substrate specificity for TAG; associated with lipid droplets
  PMID:15550674.
• The purified human enzyme has TAG lipase and acylglycerol transacylase activity
  PMID:15364929.
  Lipase activity requires the active-site serine
  PMID:16150821.
• Efficient activity requires the co-activator ABHD5/CGI-58 (the Chanarin-Dorfman gene)
  PMID:16679289.
• ATGL drives lipid droplet turnover in non-adipocytes
  PMID:16239926.
• ATGL protein levels are controlled by ubiquitination/proteasomal degradation (LDAH,
  PEX2), which is regulation OF ATGL rather than a function of ATGL
  PMID:28578400.

Secondary / in vitro activities

• Acylglycerol transacylase (mono-olein / diolein acceptors) in vitro PMID:15364929.
• Retinyl ester hydrolysis and transfer of FA from TAG to retinol in keratinocyte-oriented
  comparative study PMID:17603008.
• Phospholipase A2 activity stimulated by PEDF binding (PEDF-R model in retina)
  PMID:17032652.
  The plasma-membrane receptor model has not been integrated with the lipid-droplet
  lipase function; treated as non-core.
• FAHFA biosynthesis by transacylation (mouse and human adipose)
  PMID:35676490.
  Not proposed as a new annotation here (no GOA row; candidate for future curation).

Disease

• Biallelic PNPLA2 variants cause neutral lipid storage disease with myopathy (NLSDM)
  PMID:17187067.
  This is consistent with loss of TAG hydrolase activity on lipid droplets
  (dismech Neutral_Lipid_Storage_Myopathy: GO:0004806 + GO:0019433 DECREASED, lipid droplet).

Annotation decisions (summary)

• Core: triacylglycerol lipase activity (GO:0004806), triglyceride catabolic process
  (GO:0019433), lipid droplet (GO:0005811), lipid droplet disassembly (GO:1905691).
• Removed: lipoprotein lipase activity (Reactome DAG-hydrolysis reaction mis-mapped;
  ATGL acts on intracellular droplets, not lipoproteins), ER lumen (Reactome FAM20C
  substrate list; ATGL is cytosolic/droplet-associated), bare protein binding.
• General IEA parents (hydrolase activity, lipid (catabolic) metabolic process) and the
  InterPro-derived "positive regulation of triglyceride catabolic process" modified to the
  direct catalytic terms.