ACP2

ACP2 encodes a lysosomal acid phosphatase that, acting in concert with ACP5, dephosphorylates mannose 6-phosphate (Man6P) residues on lysosomal proteins; combined Acp2/Acp5 deficiency causes accumulation of Man6P-containing proteins in lysosomes (PMID:22158965). A principal substrate is Npc2, whose dephosphorylation by ACP2/ACP5 shifts its isoelectric point and governs its interaction with negatively charged lysosomal membranes at acidic pH, with loss of this activity producing unesterified cholesterol accumulation in lysosomes (PMID:22158965). The enzymatic activity is essential for organ development: a Gly244Glu missense mutation abolishes catalytic activity without affecting transcript stability, producing lysosomal storage and disrupting cerebellar cortex architecture and hair follicle morphology in nax mice (PMID:15503243), and Acp2 loss severely reduces cerebellar granule cell proliferation in association with downregulation of MYCN and dysregulation of SHH signaling (PMID:33804256). Beyond its lysosomal role, ACP2 is required in host cells for the membrane fusion step of influenza A virus entry, acting downstream of binding and endosomal acidification to permit viral membrane fusion, uncoating, and nuclear import of viral ribonucleoproteins (PMID:28272419).

1. 1995 Medium

   Established that a phosphatase activity designated AcP2 is differentially regulated by cGMP, resolving a catalytic step at which regulation acts.

   Evidence in vitro kinetic enzyme assays with p-nitrophenyl phosphate, comparing AcP1 and AcP2 isoenzymes

   PMID:7827101

   Open questions at the time

   • This isoenzyme designation may refer to a low-Mr cytosolic phosphatase rather than lysosomal ACP2
   • No link established to lysosomal substrates or in vivo function
2. 2004 High

   Demonstrated that ACP2 enzymatic activity is required for lysosomal homeostasis and tissue architecture, by showing a catalytically inactivating mutation causes storage pathology and developmental defects.

   Evidence positional cloning and Sanger sequencing of nax mutant mice with histological and ultrastructural analysis

   PMID:15503243

   Open questions at the time

   • Did not identify the substrates whose accumulation drives pathology
   • Mechanism linking storage to cerebellar disorganization unresolved
3. 2011 High

   Identified the molecular substrates and biochemical consequence of ACP2 activity, showing it dephosphorylates Man6P on lysosomal proteins including Npc2 to control membrane interaction and cholesterol handling.

   Evidence single, double, and combined Acp2/Acp5 knockout mice with Man6P affinity chromatography, mass spectrometry, 2D immunoblot, and hepatocyte lipid analysis

   PMID:22158965

   Open questions at the time

   • Relative contributions of ACP2 versus ACP5 to individual substrates not fully separated
   • Does not connect Npc2 dephosphorylation to the cerebellar developmental phenotype
4. 2017 Medium

   Revealed a non-lysosomal-cargo function: ACP2 is specifically required for the membrane fusion step of influenza virus entry, distinguishing fusion from binding and acidification.

   Evidence siRNA knockdown with membrane fusion, endosomal acidification, uncoating, and nuclear import assays

   PMID:28272419

   Open questions at the time

   • Molecular target of ACP2 phosphatase activity in the fusion step not identified
   • siRNA-based, single-lab study without genetic rescue
5. 2021 Medium

   Connected ACP2 loss to a developmental signaling program, showing reduced granule cell proliferation accompanied by MYCN downregulation and SHH pathway dysregulation.

   Evidence immunohistochemistry, Western blot, BrdU proliferation assays, and RT-qPCR in nax mutant mice

   PMID:33804256

   Open questions at the time

   • Causal link between lysosomal dysfunction and SHH-MYCN dysregulation not mechanistically demonstrated
   • Single-lab correlative findings
6. 2024 Low

   Implicated ACP2 in antiviral interferon signaling, with knockdown suppressing type I IFN responses and enhancing oncolytic virus replication.

   Evidence high-throughput siRNA screen with viral titer assays and RNA sequencing pathway analysis

   PMID:39550388

   Open questions at the time

   • Mechanism inferred from transcriptomics rather than direct functional assay
   • No molecular target in the IFN-1 pathway identified
   • Single-lab screen hit

• How ACP2's lysosomal phosphatase activity mechanistically connects to its roles in viral entry, interferon signaling, and SHH-MYCN-driven cerebellar development remains unresolved.
• No unified substrate explains the non-lysosomal phenotypes
• Direct phosphatase targets in viral fusion and IFN pathways unknown