Affinage

INPP5E

Phosphatidylinositol polyphosphate 5-phosphatase type IV · UniProt Q9NRR6

Length
644 aa
Mass
70.2 kDa
Annotated
2026-04-28
55 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INPP5E is a farnesylated inositol polyphosphate 5-phosphatase that hydrolyzes PtdIns(4,5)P2, PtdIns(3,4,5)P3, and PtdIns(3,5)P2 to shape phosphoinositide identity on multiple cellular membranes, with its best-characterized role being the maintenance of a PI4P-enriched, PI(4,5)P2/PI(3,4,5)P3-excluded phospholipid landscape on the primary cilium axoneme that is essential for transition zone integrity, Hedgehog/Smoothened signaling, GPR161 export, IFT-dependent cargo transport, and cilia stability (PMID:19668216, PMID:27998989, PMID:19668215, PMID:33771931). Ciliary delivery of INPP5E proceeds through a multi-step pathway in which PDE6D solubilizes the farnesylated enzyme, ARL3·GTP provides cargo-specificity-dependent release at the cilium, and ARL13B, RPGR, TULP3, ARL16, and ATG16L1 each facilitate distinct targeting or retention steps, with four conserved ciliary localization signals mediating partner engagement (PMID:23150559, PMID:27063844, PMID:24166846, PMID:36063381, PMID:35196065). Beyond cilia, INPP5E functions at lysosomes to reduce PI(3,5)P2 and promote cortactin-dependent autophagosome–lysosome fusion, at phagosomes to support Rab5/PI3P accumulation via Rab20, at centrosomes and kinetochores during mitosis to maintain genome stability, and at the immune synapse to regulate PI(4,5)P2 clearance and TCR signaling (PMID:27340123, PMID:25269936, PMID:28031327, PMID:37670137). Loss-of-function mutations in the INPP5E phosphatase domain cause the ciliopathies Joubert syndrome and MORM syndrome (PMID:19668216).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Establishing that INPP5E possesses inositol polyphosphate 5-phosphatase activity and that its C-terminal CaaX prenylation motif is functionally important for inducing morphological changes, providing the first enzymatic and structural characterization.

    Evidence Enzymatic activity assay in COS-7 cells with CaaX deletion/point mutants and morphology assays in fibroblasts

    PMID:10405344

    Open questions at the time
    • Physiological substrates in vivo not defined
    • Cellular context of CaaX-dependent signaling unknown
    • No ciliary connection yet recognized
  2. 2009 High

    Two simultaneous studies revealed that INPP5E localizes to the primary cilium axoneme, that Joubert-syndrome-causing mutations cluster in the phosphatase domain and impair catalytic activity, and that INPP5E loss destabilizes cilia in a PI3K-dependent manner — establishing the gene as a ciliopathy gene and linking its enzymatic function to ciliary homeostasis.

    Evidence Patient mutation analysis, enzymatic activity assays, Inpp5e KO mouse, PI3K inhibitor rescue of ciliary instability, immunofluorescence

    PMID:19668215 PMID:19668216

    Open questions at the time
    • Mechanism by which INPP5E reaches cilia unknown
    • Identity of lipid substrates in the cilium not resolved
    • Signaling pathways downstream of ciliary instability undefined
  3. 2011 Medium

    Gain- and loss-of-function experiments demonstrated that INPP5E negatively regulates the IGF-1/PI3K/Akt/mTORC1 signaling axis, connecting its phosphatase activity to a major growth-regulatory pathway.

    Evidence Overexpression and siRNA knockdown in cultured cells with western blot readouts for pAkt, p70S6K, and 4E-BP1

    PMID:21436142

    Open questions at the time
    • In vivo relevance not established
    • Substrate specificity in this context unclear
    • Compartment of action (cilium vs. non-cilium) not determined
  4. 2012 High

    Identification of ARL13B and PDE6D as direct binding partners required for INPP5E ciliary targeting, with Joubert-syndrome ARL13B mutations disrupting the interaction, established the first molecular framework for how INPP5E reaches the cilium.

    Evidence Co-immunoprecipitation, protein interaction mapping, ciliary targeting assays, Joubert syndrome mutant analysis

    PMID:23150559

    Open questions at the time
    • Order of PDE6D vs. ARL13B action unclear
    • Role of farnesylation in PDE6D binding not yet structurally resolved
    • Intra-ciliary retention mechanism unknown
  5. 2014 High

    Two studies refined the ciliary targeting model: PDE6D was shown to bind farnesylated INPP5E as a prenyl-dependent cargo released by ARL3·GTP, while AURKA was found to phosphorylate and activate INPP5E, linking ciliary phosphoinositide metabolism to centrosomal kinase signaling and cell division.

    Evidence Biochemical interaction assays, patient fibroblast localization, zebrafish rescue, AURKA kinase assay, 5-phosphatase activity measurement

    PMID:24166846 PMID:25395580

    Open questions at the time
    • AURKA phosphorylation sites on INPP5E not mapped
    • How AURKA-INPP5E feedback relates to ciliary vs. mitotic roles unclear
    • Phagosomal role (Rab20) identified concurrently but connection to ciliary functions unexplored
  6. 2014 Medium

    INPP5E was found to promote Rab5 and PtdIns3P accumulation on phagosomes through Rab20, establishing a non-ciliary function in phagosome maturation in macrophages.

    Evidence shRNA knockdown in RAW264.7 macrophages, phosphoinositide measurement on phagosomes, Rab5/Rab20 rescue

    PMID:25269936

    Open questions at the time
    • Whether INPP5E directly dephosphorylates a phagosomal substrate or acts indirectly unknown
    • Mechanism linking INPP5E to Rab20 recruitment undefined
    • In vivo relevance in phagocyte biology not tested
  7. 2016 High

    A burst of studies in 2016 defined the mechanistic consequences of INPP5E loss at the cilium: PI(4,5)P2 and PI(3,4,5)P3 accumulate at the transition zone disrupting scaffolding and Smoothened levels; ARL13B-INPP5E interaction is required for IFT-A-mediated retrograde trafficking and GPR161 exit; and PDE6D cargo affinity was shown structurally to determine exclusive ciliary sorting of INPP5E via ARL3·GTP (not ARL2).

    Evidence Inpp5e KO mouse, catalytic-dead mutant rescue, ARL13B KO cells, crystal structures of PDE6D-cargo complexes, structure-guided mutagenesis, localization assays

    PMID:27063844 PMID:27954 PMID:27998989

    Open questions at the time
    • How transition zone scaffold responds mechanistically to PI(4,5)P2 accumulation is unclear
    • Whether INPP5E acts on PI(4,5)P2 or PI(3,4,5)P3 preferentially in vivo not resolved
    • Structural basis of ARL13B-INPP5E interaction not determined
  8. 2016 High

    INPP5E was shown to function at lysosomes where it hydrolyzes PI(3,5)P2 to enable cortactin-dependent actin stabilization required for autophagosome–lysosome fusion, and at centrosomes/basal bodies where its product PI4P inhibits TTBK2-CEP164 interaction to regulate ciliogenesis initiation — expanding the functional repertoire well beyond the cilium.

    Evidence INPP5E knockdown in neuronal cells with lysosome fractionation and autophagy flux assay; biochemical binding assays for TTBK2/CEP164/PI4P

    PMID:26916822 PMID:27340123

    Open questions at the time
    • Whether PI(3,5)P2 is the sole lysosomal substrate unknown
    • How INPP5E toggles between ciliary and lysosomal pools unclear
    • Centrosomal PI4P regulation in cycling vs. quiescent cells not distinguished
  9. 2016 High

    INPP5E enzymatic activity was shown to regulate apical PtdIns(4,5)P2/PtdIns(3,4,5)P3 segregation and basal body docking in renal epithelia, with conditional kidney-specific Inpp5e deletion causing polycystic kidney disease through PI3K/Akt/mTORC1 hyperactivation rescued by mTORC1 inhibition.

    Evidence Zebrafish inpp5e knockdown with ezrin rescue, conditional Inpp5e KO mouse (kidney-specific) with mTORC1 inhibitor treatment

    PMID:27056978 PMID:27401686

    Open questions at the time
    • Whether renal cystogenesis is cilia-dependent or a direct PI3K/Akt effect not fully separated
    • Contribution of different PI substrates to PKD phenotype not resolved
  10. 2017 Medium

    INPP5E was found to localize to centrosomes, kinetochores, and the midzone spindle during mitosis, with its loss impairing the spindle assembly checkpoint and chromosomal integrity — establishing a cell-division role independent of cilia.

    Evidence siRNA and KO in human and murine cells, immunofluorescence for spindle/centrosome markers, cell cycle analysis

    PMID:28031327

    Open questions at the time
    • Mitotic substrates of INPP5E not identified
    • Whether phosphatase activity is required for mitotic function not tested with catalytic-dead mutants
    • Relationship between mitotic and ciliary phenotypes unclear
  11. 2018 High

    Live-cell imaging established that INPP5E ciliary transport proceeds in three mechanistically separable steps — PDE6D-dependent entry, IFT-dependent intra-ciliary transport (independent of PDE6D and farnesylation), and ciliary retention — with ARL3 moving by free diffusion.

    Evidence FRAP analysis, live fluorescence microscopy, PDE6D depletion, dynein inhibition, IFT perturbation, CaaX mutants

    PMID:29140789

    Open questions at the time
    • Identity of the IFT complex subunits mediating INPP5E transport not determined
    • Retention mechanism molecularly undefined
    • Whether ARL3 diffusion rate limits cargo release not tested
  12. 2019 Medium

    Viral infection was found to induce an Inpp5e mRNA variant lacking repressive uORFs, enhancing INPP5E translation and contributing to antiviral innate immunity by altering virus attachment — revealing a translational regulatory mechanism.

    Evidence Ribosome profiling, mRNA isoform analysis, INPP5E knockdown with virus infection assays

    PMID:31851930

    Open questions at the time
    • How INPP5E alters virus attachment mechanistically unknown
    • Generality across virus types not established
    • Whether ciliary or non-ciliary INPP5E mediates the antiviral effect unresolved
  13. 2020 High

    Genetic epistasis in mouse neural tube and cortex demonstrated that INPP5E plays both positive and negative roles in Hedgehog signaling in a cilia- and Smoothened-dependent manner, with loss reducing Gli3 repressor levels and genetically restoring Gli3R rescuing neurogenesis defects.

    Evidence Inpp5e null mouse, genetic epistasis with Gli3 and Smoothened, cortical layer and neural tube patterning analysis

    PMID:31964774 PMID:32840212

    Open questions at the time
    • How INPP5E controls the ratio of Gli activator to repressor at the lipid level not resolved
    • Whether transition zone disruption or axonemal PI changes are the primary cause unclear
  14. 2021 High

    Conditional knockout studies in olfactory neurons and photoreceptors showed that INPP5E remodels the ciliary phospholipid landscape in sensory cilia: loss redistributes PI(4,5)P2 along the entire olfactory cilium impairing odor adaptation, and in photoreceptors disrupts disc morphogenesis and IFT, causing rapid rod-cone degeneration.

    Evidence Conditional KO mice (olfactory sensory neurons, retina), phospholipid immunofluorescence, electrophysiology, electron microscopy, adenoviral gene rescue

    PMID:33711342 PMID:33771931

    Open questions at the time
    • Whether PI(4,5)P2 redistribution directly affects channel gating or acts through secondary effectors unknown
    • Disc morphogenesis defect's dependence on specific phosphoinositide species not delineated
  15. 2022 High

    Systematic mutagenesis defined four conserved ciliary localization signals (CLS1–CLS4) in INPP5E with partial redundancy, each engaging distinct combinations of trafficking partners (PDE6D, ARL13B, RPGR, TULP3, CEP164, ATG16L1), and ARL16 was identified as required for Golgi-to-cilium trafficking of INPP5E.

    Evidence CLS mutagenesis with Co-IP interaction mapping and complementation in patient cells; ARL16 KO MEFs with Golgi marker colocalization

    PMID:35196065 PMID:36063381

    Open questions at the time
    • How CLS1–CLS4 cooperate structurally during sequential trafficking steps not modeled
    • Whether ARL16 acts directly on INPP5E or through IFT140 not resolved
  16. 2023 Medium

    INPP5E was shown to localize to the immune synapse where it interacts with CD3ζ, ZAP-70, and Lck, regulates PI(4,5)P2 clearance, and is required for efficient TCR signaling and IL-2 production — establishing a non-ciliary immune function.

    Evidence Co-IP, immunofluorescence at immune synapse, siRNA knockdown, flow cytometry for phospho-signaling readouts

    PMID:37670137

    Open questions at the time
    • Whether INPP5E directly dephosphorylates PI(4,5)P2 at the synapse center or acts indirectly not tested
    • In vivo immune consequence of INPP5E deficiency in T cells unknown
    • Only single lab report
  17. 2025 High

    Inducible KO after photoreceptor outer segment formation demonstrated that INPP5E is required continuously for disc renewal, actin network maintenance at the disc morphogenesis site, and Golgi integrity, separating its role in ongoing outer segment maintenance from initial ciliogenesis.

    Evidence Conditional and inducible Inpp5e KO mice, electron microscopy, actin network imaging, rhodopsin localization

    PMID:39871753

    Open questions at the time
    • Which INPP5E substrate(s) control actin remodeling at the disc site not identified
    • Whether lipid changes precede or follow Golgi structural abnormalities unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis of the ARL13B–INPP5E interaction, the identity of INPP5E phosphoinositide substrates at mitotic structures, how INPP5E partitions between ciliary, lysosomal, centrosomal, and synaptic pools, and whether its diverse non-ciliary roles require distinct regulatory inputs or represent a shared PI-remodeling mechanism.
  • No crystal structure of ARL13B–INPP5E complex
  • Mitotic substrates and phosphorylation sites on INPP5E remain unmapped
  • Mechanism governing INPP5E distribution across compartments unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0008289 lipid binding 3
Localization
GO:0005929 cilium 9 GO:0005815 microtubule organizing center 3 GO:0005886 plasma membrane 3 GO:0005694 chromosome 1 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9709957 Sensory Perception 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
ARL13BARL3ATG16L1AURKACEP164PDE6DRPGRTULP3

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 INPP5E (pharbin) hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2; mutations clustered in the phosphatase domain impair 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localizes to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. Enzymatic activity assay, patient mutation analysis, immunofluorescence localization, ciliary stability assay in cells Nature genetics High 19668216
2009 Inpp5e is concentrated in the axoneme of the primary cilium in ciliated mouse embryonic fibroblasts. Inpp5e inactivation does not impair ciliary assembly but alters the stability of pre-established cilia after serum addition; ciliary instability is restored by blocking PI3K activity or ciliary PDGFRα, placing INPP5E downstream of PI3K signaling at cilia. Inpp5e knockout mouse model, immunofluorescence, PI3K inhibitor rescue, genetic epistasis Nature genetics High 19668215
1999 INPP5E (pharbin) possesses inositol polyphosphate 5-phosphatase catalytic activity, hydrolyzing the 5-phosphate of IP3, IP4, and PtdIns(4,5)P2. The CaaX motif at the C-terminus is required for induction of dendritic morphology in fibroblasts but not for membrane association; the protein localizes to plasma membrane-associated structures including membrane ruffles. Enzymatic activity assay in COS-7 cells, CaaX deletion/point mutants, cell morphology assay in C3H/10T1/2 fibroblasts Biochemical and biophysical research communications High 10405344
2012 INPP5E is targeted to the primary cilium through a C-terminal motif and via PDE6D (prenyl-binding protein)-dependent mechanisms. ARL13B (but not ARL2 or ARL3) facilitates ciliary targeting of INPP5E; ARL13B missense mutations causing Joubert syndrome disrupt the ARL13B–INPP5E interaction. INPP5E also interacts with CEP164, forming a distinct functional network. Co-immunoprecipitation, protein-protein interaction mapping, ciliary targeting assays, mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 23150559
2014 PDE6D binds farnesylated INPP5E as a prenyl-dependent cargo and is required for INPP5E ciliary targeting. GTP-bound ARL3 acts as a cargo-release factor for PDE6D-bound INPP5E. Mutant PDE6D (from Joubert syndrome patient) shows reduced binding to INPP5E and is unable to bind GTP-ARL3, resulting in failure of INPP5E to localize to primary cilia. Proteomic/biochemical interaction assays, patient fibroblast localization, zebrafish rescue experiments, Co-IP Human mutation High 24166846
2016 PDE6D sorts farnesylated INPP5E exclusively into cilia because INPP5E is a high-affinity cargo released only by ciliary ARL3·GTP (not by non-ciliary ARL2), establishing cargo-carrier affinity as a determinant of ciliary sorting. Structure-guided mutation converting INPP5E to a low-affinity PDE6D cargo abolishes exclusive ciliary localization. Crystal structures of PDE6D/cargo complexes, affinity measurements, structure-guided mutagenesis, cell localization assays Nature communications High 27063844
2016 INPP5E's phosphoinositide substrates PI(4,5)P2 and PI(3,4,5)P3 accumulate at the transition zone (TZ) in Hedgehog-stimulated Inpp5e-null cells, associated with reduced TZ scaffolding protein recruitment and reduced Smoothened levels at cilia. Wild-type but not 5-phosphatase-dead INPP5E restores TZ molecular organization and Smoothened accumulation, identifying INPP5E as essential for maintaining transition zone function and Hedgehog signaling at cilia. Inpp5e knockout mouse, catalytic-dead mutant rescue, immunofluorescence, genetic epistasis with Smoothened M2 expression The Journal of cell biology High 27998989
2016 INPP5E interacts with ARL13B through its C-terminal region for ciliary localization; in ARL13B-knockout cells INPP5E is mislocalized and IFT-A/B complexes accumulate at ciliary tips, preventing GPR161 exit from cilia in response to Smoothened agonist. ARL13B regulates IFT-A-mediated retrograde protein trafficking within cilia through its interaction with INPP5E. Visible immunoprecipitation assay, ARL13B KO cells, rescue with wild-type and interaction-defective mutants, immunofluorescence Journal of cell science High 27954
2016 INPP5E and PIPKIγ counteract each other at the centrosome/basal body to regulate TTBK2 recruitment for ciliogenesis initiation. INPP5E's product PtdIns(4)P accumulates at the centrosome in non-ciliated cells; PtdIns(4)P binding to TTBK2 and CEP164 inhibits the TTBK2–CEP164 interaction and prevents TTBK2 recruitment needed for CP110 removal and axoneme elongation. Biochemical binding assays, immunofluorescence, knockdown/overexpression experiments, phosphoinositide binding studies Nature communications High 26916822
2014 INPP5E interacts with AURKA (Aurora kinase A), a centrosomal kinase regulating ciliary disassembly. AURKA phosphorylates INPP5E and thereby increases its 5-phosphatase activity; increased INPP5E activity in turn promotes transcriptional downregulation of AURKA partly through an AKT-dependent mechanism, establishing a feedback loop linking AURKA and phosphoinositide signaling. Co-immunoprecipitation, kinase assay (AURKA phosphorylating INPP5E), 5-phosphatase activity assay, AKT signaling readouts Journal of cell science High 25395580
2016 In neuronal cells, INPP5E is partially localized to lysosomes where its enzymatic activity and membrane anchoring are required for autophagosome–lysosome fusion. INPP5E decreases lysosomal PI(3,5)P2 levels, which counteracts cortactin-mediated actin filament stabilization on lysosomes; actin filaments on lysosomes are required for fusion with autophagosomes. INPP5E knockdown in neuronal cells, lysosome fractionation, PI(3,5)P2 measurement, actin dynamics assay, autophagy flux assay The EMBO journal High 27340123
2016 INPP5E's enzymatic activity at the apical membrane directs apical docking of basal bodies in renal epithelia. Knockdown of inpp5e leads to defects in cell polarity, cortical F-actin organization, and apical segregation of PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Ezrin, which crosslinks PtdIns(4,5)P2 and F-actin, overexpression rescues inpp5e morphant phenotypes; PI3K inhibition also rescues defects. Zebrafish KO/knockdown, genetic rescue, PI3K inhibitor rescue, ezrin overexpression rescue, immunofluorescence Journal of the American Society of Nephrology High 27401686
2016 Inpp5e suppresses polycystic kidney disease by inhibiting the PI3K/Akt/mTORC1 signaling axis in renal epithelial cells; conditional kidney-specific Inpp5e deletion causes severe PKD with hyperactivation of PI3K/Akt and mTORC1, and mTORC1 inhibitor treatment improves kidney morphology and function without affecting cilia. Conditional Inpp5e knockout mouse (kidney-specific), phosphoprotein readouts, mTORC1 inhibitor treatment Human molecular genetics High 27056978
2018 INPP5E ciliary transport requires three steps: (1) farnesylation- and PDE6D-mediated targeting; (2) INPP5E–PDE6D complex diffusion into the cilium with transfer to the IFT system; and (3) retention inside cilia. Inner-ciliary transport of INPP5E is regulated by the IFT system independently of PDE6D and farnesylation; ARL3 moves into and within cilia by free diffusion. Live cell fluorescence microscopy, FRAP analysis, PDE6D depletion, dynein inhibition, IFT perturbation, CaaX mutants Biological chemistry High 29140789
2016 TULP3 (via its IFT-A binding activity) is required for ciliary localization of membrane-associated proteins ARL13B and INPP5E; TULP3 KO cells fail to localize ARL13B and INPP5E to cilia, rescued by wild-type TULP3 but not by an IFT-A-binding-defective mutant. TULP3 KO RPE-1 cells (CRISPR), immunofluorescence, rescue with TULP3 mutants Biochemical and biophysical research communications Medium 30583862
2011 INPP5E (pharbin) negatively regulates IGF-1/PI3K/Akt signaling: ectopic expression suppresses IGF-1-induced Akt phosphorylation and downstream p70 S6 kinase and 4E-BP1 phosphorylation and protein synthesis, while RNAi knockdown increases IGF-1-induced Akt phosphorylation. Overexpression and siRNA knockdown in cells, western blot for pAkt, p70S6K, 4E-BP1 Journal of biochemistry Medium 21436142
2014 In macrophages, Inpp5e promotes PtdIns3P and Rab5 accumulation on phagosomes through a functional interaction with Rab20; Inpp5e deficiency reduces Rab20 phagosomal association, decreasing Rab5 activity and PtdIns3P accumulation, accelerating phagosome acidification. shRNA KD in RAW264.7 macrophages, phosphoinositide measurement on phagosomes, Rab5 constitutively active rescue, Rab20 overexpression The Biochemical journal Medium 25269936
2016 RPGR interacts with PDE6D (via its C-terminus) and with INPP5E (via its N-terminus). INPP5E trafficking to cilia depends on RPGR's ciliary localization, which in turn depends on RPGR–PDE6D interaction, placing RPGR as an upstream regulator of INPP5E ciliary targeting. Proteomic and Co-IP interaction mapping, localization analysis with N-terminal RPGR deletion mutants Human molecular genetics Medium 28172980
2017 INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and to the midzone spindle at mitotic exit; its expression peaks at mitotic entry. INPP5E silencing or KO impairs the spindle assembly checkpoint, centrosome and spindle function, and chromosomal integrity, establishing a role in cell division. INPP5E siRNA and KO in human and murine cells, immunofluorescence for spindle/centrosome markers, cell cycle analysis Molecular and cellular biology Medium 28031327
2020 Inpp5e regulates Shh signaling in the neural tube by playing both positive and negative regulatory roles; Inpp5e function largely depends on the presence of cilia and on Smoothened, indicating it acts within the cilium. Inpp5e loss reduces Gli3 repressor levels, and genetically restoring Gli3 repressor rescues decreased indirect neurogenesis. Inpp5e ridge-top (rdg) null allele mouse, genetic epistasis with Gli3 and Smoothened, neural tube patterning analysis Development High 31964774
2020 Loss of Inpp5e in mouse cortical radial glial cells leads to reduced Gli3 repressor levels coinciding with ciliary structural changes, causing a transient increase in direct neurogenesis and overproduction of layer V neurons; genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis phenotype. Inpp5e KO mouse, genetic rescue with Gli3 repressor, cortical layer analysis, immunofluorescence eLife High 32840212
2021 Conditional deletion of Inpp5e in mouse olfactory sensory neurons causes dramatic remodeling of ciliary phospholipids: PI(4,5)P2 redistributes from the proximal segment to the entire cilium, PI(3,4)P2 decreases, and PI(3,4,5)P3 increases in the dendritic knob. This impairs odor adaptation; adenoviral gene replacement of Inpp5e restores both PI(4,5)P2 ciliary localization and odor response kinetics. Conditional KO mouse, phospholipid immunofluorescence in cilia, electrophysiology, adenoviral rescue Journal of cell science High 33771931
2021 Retina-specific knockout of Inpp5e causes rapid rod-cone degeneration; mutant cone outer segments contain vesicles instead of discs. Loss of INPP5E prevents assembly of axonemal and disc components and causes IFT-A and IFT-B particle accumulation at the distal ends of connecting cilia, indicating disrupted intraflagellar transport. Retina-specific conditional KO mouse (Inpp5eF/F;Six3Cre), electron microscopy, IFT complex localization, immunofluorescence The Journal of biological chemistry High 33711342
2021 ATG16L1 interacts with INPP5E and is required for proper INPP5E trafficking to the primary cilium. In ATG16L1-deficient cells, the ciliary membrane accumulates PI(4,5)P2 while PI4P (normally concentrated in the PC) is absent, indicating ATG16L1 contributes to INPP5E-mediated phosphoinositide homeostasis at cilia. Co-IP, ATG16L1 KO cells, phospholipid reporters in cilia (immunofluorescence), IFT20 co-transport assay Cell reports Medium 33910006
2022 INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four conserved ciliary localization signals (CLS1: LLxPIR; CLS2: W383; CLS3: FDRxLYL; CLS4: CaaX box) with partial redundancy. CLS4 recruits PDE6D, RPGR, and ARL13B; CLS2–CLS3 regulate TULP3, ARL13B, and CEP164 association; CLS1 and CLS4 cooperate in ATG16L1 binding. Mutagenesis of CLSs, ciliary targeting assays, Co-IP interaction mapping, complementation in patient-derived cells eLife High 36063381
2022 ARL16 is required for trafficking of INPP5E (and IFT140) from the Golgi to cilia; in Arl16 KO MEFs, both INPP5E and IFT140 accumulate at the Golgi rather than localizing to cilia, while other IFT proteins are unaffected, indicating a specific Golgi-to-cilia trafficking pathway for INPP5E. ARL16 KO in MEFs, subcellular fractionation, immunofluorescence for INPP5E, IFT140, and Golgi markers Molecular biology of the cell Medium 35196065
2023 INPP5E is enriched at the immune synapse in T cells, forms a complex with CD3ζ, ZAP-70, and Lck, and regulates PI(4,5)P2 clearance at the synapse center. INPP5E silencing impairs polarized CD3ζ distribution at the synapse, reduces CD3ζ and ZAP-70 phosphorylation, and attenuates IL-2 secretion. Co-immunoprecipitation, immunofluorescence at immune synapse, siRNA knockdown, flow cytometry for signaling readouts Communications biology Medium 37670137
2025 Conditional and inducible KO of Inpp5e in mouse photoreceptors (after outer segment formation) causes outer segment shortening, reduction in newly forming discs, Golgi structural abnormalities, mislocalized rhodopsin, accumulation of extracellular vesicles, and disruption of the actin network at the disc morphogenesis site, demonstrating INPP5E is required for ongoing outer segment renewal. Conditional and inducible Inpp5e KO mice, electron microscopy, immunofluorescence, actin network imaging Journal of cell science High 39871753
2019 Viral infection induces expression of an Inpp5e mRNA variant lacking repressive upstream open reading frames (uORFs), enabling enhanced INPP5E translation. INPP5E contributes to antiviral innate immunity by altering virus attachment. Translatome analysis (ribosome profiling), mRNA isoform analysis, INPP5E knockdown with virus infection assays Cell reports Medium 31851930

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nature genetics 342 19668216
2009 INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nature genetics 295 19668215
2012 ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proceedings of the National Academy of Sciences of the United States of America 196 23150559
2014 A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Human mutation 108 24166846
2016 Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome. The EMBO journal 104 27340123
2016 INPP5E regulates phosphoinositide-dependent cilia transition zone function. The Journal of cell biology 95 27998989
2016 Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E. Journal of cell science 80 27927754
2016 Phosphatidylinositol phosphate kinase PIPKIγ and phosphatase INPP5E coordinate initiation of ciliogenesis. Nature communications 73 26916822
2014 INPP5E interacts with AURKA, linking phosphoinositide signaling to primary cilium stability. Journal of cell science 71 25395580
2016 PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nature communications 68 27063844
2013 Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. European journal of human genetics : EJHG 57 23386033
2018 TULP3 is required for localization of membrane-associated proteins ARL13B and INPP5E to primary cilia. Biochemical and biophysical research communications 51 30583862
2016 Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling. Human molecular genetics 46 27056978
2015 MKS1 regulates ciliary INPP5E levels in Joubert syndrome. Journal of medical genetics 42 26490104
2016 The Joubert Syndrome Protein Inpp5e Controls Ciliogenesis by Regulating Phosphoinositides at the Apical Membrane. Journal of the American Society of Nephrology : JASN 41 27401686
2015 Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 41 26748598
2017 A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma. Oncogene 40 28650469
2016 Prenylated retinal ciliopathy protein RPGR interacts with PDE6δ and regulates ciliary localization of Joubert syndrome-associated protein INPP5E. Human molecular genetics 36 28172980
2012 Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish. Vision research 35 23022135
1999 Pharbin, a novel inositol polyphosphate 5-phosphatase, induces dendritic appearances in fibroblasts. Biochemical and biophysical research communications 35 10405344
2021 Deletion of the phosphatase INPP5E in the murine retina impairs photoreceptor axoneme formation and prevents disc morphogenesis. The Journal of biological chemistry 25 33711342
2022 Multiple ciliary localization signals control INPP5E ciliary targeting. eLife 23 36063381
2021 The autophagy protein ATG16L1 cooperates with IFT20 and INPP5E to regulate the turnover of phosphoinositides at the primary cilium. Cell reports 23 33910006
2020 The ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling. Development (Cambridge, England) 21 31964774
2018 Mechanism and dynamics of INPP5E transport into and inside the ciliary compartment. Biological chemistry 21 29140789
2017 Defective ciliogenesis in INPP5E-related Joubert syndrome. American journal of medical genetics. Part A 21 29052317
2016 Regulation of lysosomal phosphoinositide balance by INPP5E is essential for autophagosome-lysosome fusion. Autophagy 21 27715391
2021 Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD. NPJ genomic medicine 20 34188062
2021 INPP5E controls ciliary localization of phospholipids and the odor response in olfactory sensory neurons. Journal of cell science 18 33771931
2020 A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development. eLife 18 32840212
2020 Defective INPP5E distribution in NPHP1-related Senior-Loken syndrome. Molecular genetics & genomic medicine 17 33306870
2019 Induction of an Alternative mRNA 5' Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection. Cell reports 16 31851930
2017 Upregulation of miR‑598 promotes cell proliferation and cell cycle progression in human colorectal carcinoma by suppressing INPP5E expression. Molecular medicine reports 16 29257251
2014 Inpp5e increases the Rab5 association and phosphatidylinositol 3-phosphate accumulation at the phagosome through an interaction with Rab20. The Biochemical journal 16 25269936
2021 The Major Ciliary Isoforms of RPGR Build Different Interaction Complexes with INPP5E and RPGRIP1L. International journal of molecular sciences 15 33808286
2022 Phylogenetic profiling and cellular analyses of ARL16 reveal roles in traffic of IFT140 and INPP5E. Molecular biology of the cell 13 35196065
2022 The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling. Cell reports 13 35584663
2011 Regulation of IGF-1/PI3K/Akt signalling by the phosphoinositide phosphatase pharbin. Journal of biochemistry 12 21436142
2022 TMEM67 is required for the gating function of the transition zone that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia. Biochemical and biophysical research communications 11 36334440
2019 BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan. Annals of human genetics 11 31173343
2022 INPP5E and Coordination of Signaling Networks in Cilia. Frontiers in molecular biosciences 10 35463949
2017 INPP5E Preserves Genomic Stability through Regulation of Mitosis. Molecular and cellular biology 9 28031327
2021 Down-Regulation of Inpp5e Associated With Abnormal Ciliogenesis During Embryonic Neurodevelopment Under Inositol Deficiency. Frontiers in neurology 7 34093381
2021 Novel Insights Into Monogenic Obesity Syndrome Due to INPP5E Gene Variant: A Case Report of a Female Patient. Frontiers in endocrinology 7 34211432
2018 A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs. PloS one 7 30235266
2017 A Homozygous Missense Variant in INPP5E Associated with Joubert Syndrome and Related Disorders. Molecular syndromology 6 29230161
2023 INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control. Communications biology 5 37670137
2025 Inpp5e is crucial for photoreceptor outer segment maintenance. Journal of cell science 4 39871753
2024 Inpp5e Regulated the Cilium-Related Genes Contributing to the Neural Tube Defects Under 5-Fluorouracil Exposure. Molecular neurobiology 4 38285286
2024 Utilization of automated cilia analysis to characterize novel INPP5E variants in patients with non-syndromic retinitis pigmentosa. European journal of human genetics : EJHG 3 38806661
2025 Regulation of INPP5E in Ciliogenesis, Development, and Disease. International journal of biological sciences 2 39781470
2024 INPP5E Regulates the Distribution of Phospholipids on Cilia in RPE1 Cells. Journal of clinical laboratory analysis 1 38514901
2026 The EH Binding protein EHBP1 operates in a ciliary functional module affected by INPP5E dysfunction. Journal of cell science 0 41805112
2025 Longitudinal Multimodal Assessment of Structure and Function in INPP5E-Related Retinopathy. Genes 0 41465079
2024 Inpp5e Is Critical for Photoreceptor Outer Segment Maintenance. bioRxiv : the preprint server for biology 0 39253441