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WDR45B

WD repeat domain phosphoinositide-interacting protein 3 · UniProt Q5MNZ6

Length
344 aa
Mass
38.1 kDa
Annotated
2026-06-11
9 papers in source corpus 7 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WDR45B (WIPI3) is a PI3P-binding β-propeller scaffold that operates at multiple steps of autophagy and lysosomal mTOR signalling, and is essential for neuronal homeostasis (PMID:28561066, PMID:31238825). It acts as a lysosomal recruitment factor for the TSC complex: a cryo-EM structure of human TSC bound to WIPI3 resolves an amino-terminal TSC1 HEAT-repeat dimer forming a monophosphoinositide-binding pocket, showing how WIPI3 and PIP signalling cooperate to dock TSC at the lysosomal membrane to inhibit mTORC1 (PMID:39565846), consistent with its earlier identification scaffolding LKB1-AMPK-TSC signalling at lysosomes and forming a complex with FIP200 at nascent autophagosomes (PMID:28561066). Beyond mTOR regulation, WDR45B is also required for autophagosome maturation: it binds the tether protein EPG5 and targets it to late endosomes/lysosomes to promote SNARE-dependent autophagosome-lysosome fusion, a function abolished by disease-causing mutations that impair EPG5 binding (PMID:33636118, PMID:34105435). It is additionally essential for alternative, Atg5/Atg7-independent autophagy through binding Golgi membranes to generate isolation membranes (PMID:33082312). In mice, Wdr45b loss causes accumulation of SQSTM1- and ubiquitin-positive aggregates, swollen axons, and cerebellar neuronal loss, and it functions cooperatively with the paralog WDR45, with double knockouts being neonatally lethal (PMID:31238825, PMID:33082312).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2017 Medium

    Established WIPI3 as a signalling scaffold upstream of PtdIns3P production rather than a purely downstream PI3P effector, linking it to AMPK-TSC-mTOR control and to FIP200 at nascent autophagosomes.

    Evidence WIPI interactome by Co-IP/mass spectrometry, functional kinase screen, and localization in cells

    PMID:28561066

    Open questions at the time
    • No structural model of the WIPI3-TSC or WIPI3-FIP200 contacts
    • Single lab, no in vitro reconstitution
    • Direct vs indirect nature of the AMPK-TSC association not resolved
  2. 2019 Medium

    Demonstrated that WDR45B is required for neural autophagy and acts cooperatively with its paralog WDR45, defining a non-redundant but overlapping role.

    Evidence Wdr45b knockout mice with autophagy-substrate histology and Wdr45b/Wdr45 double-KO genetic epistasis

    PMID:31238825

    Open questions at the time
    • Molecular step in autophagy disrupted not pinpointed
    • Basis of cooperativity with WDR45 unresolved
    • Single lab
  3. 2020 High

    Showed WDR45B has an autophagy-step function distinct from canonical macroautophagy by being essential for Atg5/Atg7-independent alternative autophagy at the Golgi.

    Evidence Neuron-specific Wipi3-KO mice, EM, Golgi localization by fractionation, Atg7/Wipi3 double-KO lethality, and Dram1 rescue

    PMID:33082312

    Open questions at the time
    • Mechanism of isolation-membrane generation from Golgi not defined
    • How iron/ceruloplasmin accumulation links to the autophagy defect unclear
  4. 2021 High

    Identified a discrete maturation-stage role: WDR45B targets the tether EPG5 to late endosomes/lysosomes to promote SNARE-dependent fusion, and connected disease mutations to loss of this interaction.

    Evidence Reciprocal Co-IP, Wdr45/Wdr45b double-KO neural cells, maturation assays, SNARE complex analysis, ATG2A and O-GlcNAcylation-inhibition rescues; replicated in companion paper

    PMID:33636118 PMID:34105435

    Open questions at the time
    • Structural basis of WDR45B-EPG5 binding not resolved
    • How a single scaffold coordinates both early signalling and late fusion roles unclear
  5. 2024 High

    Provided the structural mechanism for WIPI3 as a lysosomal recruitment factor for TSC, revealing a TSC1 HEAT-repeat PIP-binding pocket that, with WIPI3, docks TSC to inhibit mTORC1.

    Evidence 2.8-Å cryo-EM structure of human TSC:WIPI3 with biochemical reconstitution

    PMID:39565846

    Open questions at the time
    • In vivo contribution of WIPI3-dependent TSC recruitment to mTORC1 output not quantified
    • Interplay with the LKB1-AMPK arm not structurally addressed
  6. 2025 Medium

    Defined WIPI3 as a PI3P-dependent membrane anchor that bridges the ATG13:ATG101 HORMA dimer to membranes to recruit and activate ULK1 during autophagosome initiation.

    Evidence In vitro complex reconstitution, molecular dynamics, ATG16L1 phosphorylation assay, ATG13 puncta and autophagic flux measurements (preprint)

    PMID:bio_10.1101_2025.11.07.687251

    Open questions at the time
    • Not yet peer-reviewed
    • Functional redundancy with WIPI2 at this step not delineated
    • In vivo requirement of the WIPI3:ATG13 contact untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single β-propeller scaffold is partitioned among its distinct lysosomal mTOR, initiation, alternative-autophagy, and fusion roles in a given cell remains unresolved.
  • No spatiotemporal map of which complex WDR45B occupies at each autophagy stage
  • Determinants selecting EPG5 vs TSC vs ATG13 partners unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 2
Partners
ATG101ATG13EPG5FIP200TSC1WDR45
Complex memberships
ATG13:ATG101 HORMA dimerEPG5-SNARE fusion machineryTSC complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 WIPI3 (WDR45B) scaffolds LKB1-AMPK-TSC signalling upstream of PtdIns3P production: WIPI3 associates with AMPK-activated TSC complex at lysosomes to regulate mTOR, and forms a complex with FIP200 at nascent autophagosomes to control their size. WIPI interactome analysis (co-immunoprecipitation/mass spectrometry), functional kinase screen, localization studies Nature communications Medium 28561066
2021 WDR45B is specifically required for autophagosome maturation into autolysosomes in neural cells: WDR45B interacts with the tether protein EPG5 and targets it to late endosomes/lysosomes to promote autophagosome-lysosome fusion; disease-related mutations of WDR45B fail to rescue autophagy defects due to impaired EPG5 binding. In Wdr45/45b-depleted cells, formation of the SNARE-EPG5 fusion machinery is dampened. Co-immunoprecipitation (WDR45B–EPG5 interaction), Wdr45/Wdr45b double knockout mouse neural cells, autophagosome maturation assays, rescue with ATG2A overexpression, SNARE complex analysis, O-GlcNAcylation inhibition rescue Current biology : CB High 33636118 34105435
2019 WDR45B is critical for neural autophagy and acts cooperatively with WDR45: Wdr45b knockout mice accumulate SQSTM1- and ubiquitin-positive aggregates in brain regions and exhibit swollen axons; Wdr45b/Wdr45 double KO mice die within one day of birth with more severe autophagy defects than either single KO, establishing cooperative function in autophagy. Wdr45b knockout mouse model (histology, immunohistochemistry for autophagy substrates, behavioral tests), double KO genetic epistasis Autophagy Medium 31238825
2020 Wipi3 (WDR45B) is essential for alternative (Atg5/Atg7-independent) autophagy: Wipi3 binds to Golgi membranes and is required for generation of isolation membranes in alternative autophagy. Neuron-specific Wipi3-deficient mice show cerebellar neuronal loss and iron/ceruloplasmin accumulation suppressed by Dram1 expression. Atg7/Wipi3 double-deficient mice are mostly embryonic lethal, indicating Wipi3 maintains neuronal cells via mechanisms distinct from canonical autophagy. Neuron-specific Wipi3-knockout mice, electron microscopy, subcellular fractionation/localization to Golgi membranes, genetic epistasis (Atg7/Wipi3 double KO), rescue by Dram1 expression Nature communications High 33082312
2024 Cryo-EM structure of the complete human TSC in complex with WIPI3 (WDR45B) at 2.8 Å resolution: WIPI3 serves as a lysosomal recruitment factor for TSC; a previously undetected amino-terminal TSC1 HEAT repeat dimer forms a PIP-binding pocket that specifically binds monophosphorylated PIPs, providing a structural model by which WIPI3 and PIP-signaling networks coordinate to recruit TSC to the lysosomal membrane to inhibit mTORC1. Cryo-electron microscopy (2.8-Å structure), biochemical reconstitution of TSC:WIPI3 complex Science advances High 39565846
2025 WIPI3 (WDR45B) forms a tight complex with the ATG13:ATG101 HORMA domain heterodimer; bound to WIPI3 (or WIPI2), ATG13:ATG101 aligns with the membrane to insert its WF finger. WIPI3:ATG13 engagement is required for ATG16L1 phosphorylation by ULK1, ATG13 puncta formation, and bulk autophagic flux, establishing WIPI3 as a PI3P-dependent membrane anchor that recruits the ULK1 kinase domain to the membrane surface. Biochemical reconstitution (in vitro complex assembly), molecular dynamics simulations, cell-based phosphorylation assay (ATG16L1 phosphorylation), ATG13 puncta formation assay, autophagic flux measurement bioRxivpreprint Medium bio_10.1101_2025.11.07.687251

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Nature communications 173 28561066
2021 β-propeller proteins WDR45 and WDR45B regulate autophagosome maturation into autolysosomes in neural cells. Current biology : CB 53 33636118
2019 Role of Wdr45b in maintaining neural autophagy and cognitive function. Autophagy 49 31238825
2020 Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration. Nature communications 44 33082312
2017 WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: A consistent neurodevelopmental syndrome. Clinical genetics 36 28503735
2021 The BPAN and intellectual disability disease proteins WDR45 and WDR45B modulate autophagosome-lysosome fusion. Autophagy 14 34105435
2021 A Dictyostelium model for BPAN disease reveals a functional relationship between the WDR45/WIPI4 homolog Wdr45l and Vmp1 in the regulation of autophagy-associated PtdIns3P and ER stress. Autophagy 13 34328055
2024 Structure of the human TSC:WIPI3 lysosomal recruitment complex. Science advances 7 39565846
2022 A homozygous variant of WDR45B results in global developmental delay: Additional case and literature review. Molecular genetics & genomic medicine 1 35962600

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