INPP5E (Q9NRR6) curation notes

Deep research status

just deep-research-falcon human INPP5E first failed (falcon timed out at 600 s; perplexity-lite fallback unavailable in this environment). Re-run with --timeout 2400 succeeded: see INPP5E-deep-research-falcon.md.

Summary of function

• Type IV 5-phosphatase specific for lipid substrates PMID:10764818 with the highest PI(3,4,5)P3 affinity of known 5-phosphatases (Km 0.65 uM).
• UniProt also lists PI(3,5)P2 (by similarity) and low-affinity Ins(1,4,5)P3 hydrolysis (PMID:40969890; cached abstract is about synaptojanin-1 and does not mention INPP5E).
• Joubert syndrome mutations impair activity PMID:19668216; INPP5E localizes to cilia PMID:19668216.
• Mouse: axonemal localization; loss destabilizes pre-formed cilia but not assembly PMID:19668215
• Sets ciliary lipid identity [PMID:26305592 "Thus, Inpp5e limits ciliary PI(4,5)P2 and generates ciliary PI(4)P, consistent with a role in converting PI(4,5)P2 to PI(4)P within cilia."; PMID:26190144 "Upon INPP5E inactivation, PI(4,5)P2 accumulates at the ciliary tip whereas PI4P is depleted."], restricting TULP3/GPR161 PMID:26305592
• Delivered to cilia as farnesylated PDE6D cargo PMID:24166846.

Key decisions

• Core MF: GO:0004439 (PI(4,5)P2 5-phosphatase) and GO:0034485 (PI(3,4,5)P3 5-phosphatase); process GO:0046856.
• GO:0004445 (compound soluble inositol-polyphosphate term) MODIFY -> lipid 5-phosphatase terms.
• REMOVE: PI(3,4,5)P3 3-phosphatase (wrong position), negative regulation of translation (no basis), 14-3-3 protein binding rows.
• Reactome PI biosynthetic process MODIFY -> phosphatidylinositol dephosphorylation.
• NEW: ciliary membrane (GO:0060170), ISS from mouse data (PMID:26305592).

HPA cilium atlas vs module role

• Module (stage 5): ciliary PI(4,5)P2 5-phosphatase (GO:0004439) located in ciliary membrane.
• HPA v25: no cilium/basal body call; main location Golgi apparatus. No HPA-sourced GOA rows.
• Interpretation: the Golgi call agrees with the documented Golgi-stack pool (UniProt, by similarity). The absence of an HPA primary-cilium call conflicts with robust ciliary localization of INPP5E in human and mouse literature; it may reflect antibody performance in the HPA cell lines or cell-type heterogeneity of the ciliary proteome reported by the atlas PMID:41005307. core_functions agree with the module (PI(4,5)P2 5-phosphatase in the ciliary membrane), adding PI(3,4,5)P3 5-phosphatase activity.

Additional points from deep research (falcon)

• Cellular evidence for a third reaction, PI(3,5)P2 -> PI(3)P, comes from a neuronal lysosomal INPP5E pool needed for autophagosome-lysosome fusion (Hasegawa et al. 2016; not cached) [deep research: "In neuronal lysosomes, experimental evidence supports a third reaction"]. PI3P biosynthetic process and PI(3,5)P2 5-phosphatase rows were therefore kept as non-core rather than marked over-annotated.
• Dyson et al. 2017 (not cached): PI(4,5)P2 and PI(3,4,5)P3 accumulate at the transition zone of Inpp5e-null cells after Hh stimulation; catalytic activity is needed to restore transition-zone organization.
• Ciliary targeting signals include LLxPIR, W383, FDRxLYL and CaaX.