| 2016 |
C. elegans SORF-1 (WDR91 ortholog) and SORF-2 (WDR81 ortholog) act in a complex with BEC-1/Beclin1 to inhibit PI3-kinase complex activity, thereby preventing excessive PtdIns3P synthesis on early endosomes; loss of sorf-1 or sorf-2 leads to greatly elevated endosomal PtdIns3P and excessive early endosome fusion, blocking early-to-late endosome conversion. In mammalian cells, WDR91 and WDR81 physically interact with Beclin1 and inhibit PI3K complex activity; their inactivation causes Beclin1-dependent enlargement of PtdIns3P-enriched endosomes and defective EGFR degradation. |
Genetic loss-of-function in C. elegans, epistasis with Rab switching genes, co-immunoprecipitation (complex with Beclin1), PI3K activity assay, mammalian cell inactivation with EGFR degradation readout, live imaging of endosomal PtdIns3P |
The Journal of cell biology |
High |
26783301
|
| 2017 |
WDR91 is a Rab7 effector: it is recruited to endosomes by interacting with GTP-Rab7, and once there it inhibits Rab7-associated PI3-kinase activity to reduce PtdIns3P levels, coupling Rab switching with PtdIns3P down-regulation during early-to-late endosome conversion. Loss of WDR91 in mouse neurons causes accumulation of giant intermediate endosomes and reduced neurite length/complexity; phenotypes are rescued by wild-type WDR91 but not by Rab7-binding-deficient WDR91 mutants. Global Wdr91 knockout causes neonatal death; brain-specific inactivation impairs brain development and causes postnatal death. |
Co-immunoprecipitation with GTP-Rab7, in vitro PI3K activity assay, conditional knockout mouse models (global and brain-specific), rescue experiments with WDR91 mutants, live-cell imaging of endosomal PtdIns3P, neuronal morphology analysis |
The Journal of cell biology |
High |
28860274
|
| 2016 |
WDR81 (partner of WDR91) is required for trafficking and lysosomal degradation of tetherin and EGFR; WDR81 and WDR91 function together as a complex in endolysosomal fusion. Absence of WDR81 results in swollen endolysosomal compartments with enlarged early and late endosomes and reduced delivery of endocytosed dextran to cathepsin-active lysosomes. |
Forward genetic haploid cell screen (KBM7), functional complementation, endosomal trafficking and degradation assays, fluorescence microscopy of endolysosomal compartments |
Traffic (Copenhagen, Denmark) |
Medium |
27126989
|
| 2022 |
WDR91 specifies the endosomal retrieval subdomain required for retromer-dependent recycling. WDR91 interacts with sorting nexins (SNXs) through their PX domain and with VPS35, promoting their interaction with Rab7. WDR91 also interacts with the WASH subunit FAM21. In WDR91-deficient cells, Rab7, SNX-retromer, and FAM21 fail to localize to endosomal subdomains and endosomal actin organization is impaired; re-expression of WDR91 rescues Rab7, SNX-retromer, and FAM21 concentration at WDR91-specific subdomains where retromer-mediated membrane tubulation and release occur. |
Co-immunoprecipitation (WDR91–SNX PX domain, WDR91–VPS35, WDR91–FAM21), WDR91 knockout cells, rescue/re-expression experiments, fluorescence live imaging of endosomal subdomains, actin organization assay |
The Journal of cell biology |
High |
36190447
|
| 2024 |
Crystal structure of the human WDR91 WD40 domain in complex with Rab7 reveals an unusual interface at the C-terminus of the Rab7 switch II region; WDR91 is highly selective for Rab7 among tested GTPases. A LIS1 homology (LisH) motif in the WDR91 N-terminal domain mediates self-association and contributes to augmented full-length WDR91–Rab7 interaction. Both the Rab7-binding site and the LisH motif are indispensable for WDR91 function in endocytic trafficking. The WDR91 ortholog SORF1 lacks the WD40 domain and instead uses a C-terminal amphipathic helix for membrane targeting via interactions with acidic lipids. |
X-ray crystallography (WDR91 WD40–Rab7 co-crystal), GTPase selectivity assays, biochemical self-association assay (LisH motif), liposome interaction assay (SORF1 amphipathic helix), structure-guided mutagenesis with endocytic trafficking functional readout |
Structure (London, England : 1993) |
High |
39426373
|
| 2023 |
A first-in-class small-molecule ligand for WDR91 was discovered; co-crystal structure confirmed binding to the WDR domain side pocket in proximity to cysteine 487, enabling development of covalent analogues confirmed by intact mass LC-MS. This structural data defines a druggable pocket on the WDR91 WD40 domain. |
DNA-encoded chemical library selection, machine learning virtual screening, surface plasmon resonance (KD ~6 μM), X-ray co-crystallography, intact mass LC-MS for covalent adduct confirmation |
Journal of medicinal chemistry |
High |
37996079
|
| 2025 |
WDR91 depletion significantly inhibits productive ASO (antisense oligonucleotide) activity in melanoma cells, establishing WDR91-dependent endosomal maturation as required for productive intracellular ASO trafficking and escape from the endosomal compartment. |
Genome-wide CRISPR-Cas9 screen in melanoma cells with ASO activity readout, validation by WDR91 depletion with functional ASO potency assay |
Molecular therapy. Nucleic acids |
Medium |
40529297
|
| 2022 |
WDR91 (along with WDR81, RAB7, and CCZ1) was identified as a required host factor for late-penetrating virus (reovirus and VSV-EBO GP) infection in a CRISPR-Cas9 screen; loss of WDR81 (WDR91 complex partner) caused accumulation of viral particles in dead-end endosomal compartments, consistent with a role for the WDR81-WDR91 complex in late endosome maturation required for viral penetration. |
Genome-wide CRISPR-Cas9 knockout screen, complementation with human WDR81, viral infection assays (reovirus, VSV, VSV-EBO GP), fluorescence microscopy of viral particles in endosomes |
PLoS pathogens |
Medium |
35320319
|
| 2021 |
C5orf51 (a MON1-CCZ1 complex component) was identified as an interactor of GDP-locked RAB7A and of MON1/CCZ1 (the RAB7A GEF complex); in the absence of C5orf51, RAB7A fails to localize to depolarized mitochondria during mitophagy and is degraded by the proteasome. WDR91 is noted as part of the RAB7A regulatory network but is not a direct subject of mechanistic study in this paper. |
Proximity-dependent biotinylation (miniTurbo), co-immunoprecipitation, KO cell lines, fluorescence microscopy of RAB7A on depolarized mitochondria, proteasome inhibitor experiments |
Autophagy |
Low |
34432599
|