LRRC45

LRRC45 is a centriolar protein that functions in centrosome architecture and ciliogenesis (PMID:30131441, PMID:39882846). At the distal appendages of the mother centriole it is recruited by the core appendage proteins Cep83 and SCLT1 and in turn recruits the keratin-binding protein FBF1, placing it within the hierarchical distal-appendage assembly network (PMID:30131441, PMID:39882846). Functionally, LRRC45 promotes early ciliogenesis in CP110-uncapped centrioles by organizing centriolar satellites, establishing the transition zone, and promoting docking of Rab8-positive vesicles, while being dispensable for CP110 removal and for docking of early ciliary vesicles (PMID:30131441). It also acts as a centrosome linker component, interacting with CCDC102B downstream of C-Nap1/CEP250 to support rootletin filament formation and centrosome cohesion (PMID:30404835), and localizes to the basal body of both primary and motile cilia across differentiated and stem cell types (PMID:30131441). Biallelic loss-of-function variants in LRRC45 impair ciliogenesis, with patient fibroblasts showing reduced LRRC45 mRNA/protein and reduced cilia frequency and length, establishing a ciliopathy-associated role (PMID:39638757). Independently of its centriolar function, LRRC45 competitively binds KEAP1 to inhibit ubiquitin-proteasome degradation of NRF2, enhancing NRF2 nuclear translocation and anti-ferroptotic activity in bladder cancer (PMID:39522565), and drives proliferation and metastasis through c-MYC/Slug and MMP2/MMP9 in lung adenocarcinoma (PMID:39326735).

1. 2018 High

   Established where LRRC45 sits in the distal-appendage recruitment hierarchy, answering how it is targeted to the mother centriole and what it recruits in turn.

   Evidence Localization and epistasis/recruitment-hierarchy experiments in cultured cells

   PMID:30131441

   Open questions at the time

   • Molecular nature of the Cep83-SCLT1 binding interface not defined
   • Direct versus indirect recruitment of FBF1 not resolved
2. 2018 High

   Defined which specific ciliogenesis steps require LRRC45, distinguishing its role in transition zone and satellite organization and Rab8 vesicle docking from steps it does not control.

   Evidence siRNA knockdown with functional readouts for transition zone assembly, centriolar satellite organization, Rab8 vesicle docking, and CP110 removal

   PMID:30131441

   Open questions at the time

   • Mechanism by which LRRC45 organizes satellites unknown
   • Direct effectors linking LRRC45 to Rab8 vesicle docking not identified
3. 2018 Medium

   Showed LRRC45 broadly localizes to the basal body across primary and motile cilia and multiple cell types, indicating a general rather than cell-type-restricted ciliary function.

   Evidence Immunofluorescence across differentiated and stem cells

   PMID:30131441

   Open questions at the time

   • Functional contribution in motile cilia not tested
   • Quantitative localization dynamics across the cell cycle not addressed
4. 2018 Medium

   Connected LRRC45 to the centrosome cohesion machinery, showing it interacts with CCDC102B within the C-Nap1/rootletin linker, expanding its role beyond ciliogenesis.

   Evidence Co-immunoprecipitation, localization, and siRNA knockdown with centrosome cohesion phenotype

   PMID:30404835

   Open questions at the time

   • Direct binding between LRRC45 and CCDC102B not biochemically reconstituted
   • Whether LRRC45 is required for rootletin filament formation independent of CCDC102B unclear
5. 2020 Medium

   Defined pathway independence between LRRC45 and Cep44, ruling out mutual dependence in centrosomal recruitment and clarifying the modularity of the appendage network.

   Evidence siRNA knockdown with immunofluorescence readout of centrosomal protein levels

   PMID:31974111

   Open questions at the time

   • Functional interplay during ciliogenesis not tested
   • Single-method negative finding
6. 2023 Medium

   Systematic CRISPR knockout mapping (preprint) positioned LRRC45 within the multi-step distal-appendage assembly network and its dependence on upstream components.

   Evidence CRISPR-Cas9 knockouts, localization, and functional cilia-formation assays (preprint)

   PMID:36711481

   Open questions at the time

   • Superseded by peer-reviewed version
   • Precise step-by-step requirements still being resolved at this stage
7. 2024 Medium

   Provided human genetic evidence that LRRC45 loss-of-function impairs ciliogenesis, linking the gene to disease through reduced cilia frequency and length in patient cells.

   Evidence Exome sequencing, RT-PCR splicing analysis, Western blot, and immunofluorescence in patient-derived fibroblasts

   PMID:39638757

   Open questions at the time

   • Full clinical phenotype spectrum not delineated in this corpus
   • Rescue of the cilia defect not demonstrated
8. 2024 Medium

   Identified a non-centriolar function: LRRC45 competitively binds KEAP1 to stabilize NRF2, defining a mechanism for its anti-ferroptotic, pro-tumorigenic activity.

   Evidence Co-IP, siRNA knockdown, NRF2 stability/degradation assay, nuclear fractionation, and ferroptosis assay in bladder cancer cells

   PMID:39522565

   Open questions at the time

   • KEAP1 binding interface and competitive site not mapped
   • Relationship between centriolar and KEAP1-NRF2 functions unknown
9. 2024 Medium

   Placed c-MYC/Slug and MMP2/MMP9 downstream of LRRC45 in driving proliferation and metastasis in lung adenocarcinoma via rescue epistasis.

   Evidence siRNA knockdown, western blot, colony formation, migration assay, rescue overexpression, and xenograft mouse model

   PMID:39326735

   Open questions at the time

   • Direct molecular link between LRRC45 and c-MYC/Slug induction not defined
   • Whether this acts through the KEAP1-NRF2 axis untested

• How LRRC45's centriolar/ciliary scaffolding role mechanistically relates to its KEAP1-NRF2 and oncogenic signaling functions remains unresolved.
• No unifying mechanism connecting centrosomal and cancer-signaling roles
• No structural model of LRRC45 interactions
• Substrate or enzymatic activity, if any, undefined