LRRC45

LRRC45 is a centrosome-associated leucine-rich repeat protein that functions in both centrosome cohesion and primary ciliogenesis. At the proximal centriole, LRRC45 participates in the proteinaceous centrosome linker together with rootletin, C-Nap1, and CCDC102B to maintain centrosome cohesion (PMID:30404835, PMID:31974111). At the mother centriole, LRRC45 is recruited to distal appendages by CEP83–SCLT1, where it recruits FBF1, organizes centriolar satellites, establishes the ciliary transition zone, and promotes Rab8-positive vesicle docking to drive ciliogenesis (PMID:30131441, PMID:39882846). Biallelic loss-of-function variants in LRRC45 cause reduced primary cilia frequency and length in patient-derived fibroblasts, establishing LRRC45 as a human ciliopathy gene (PMID:39638757).

1. 2018 High

   Determining where LRRC45 sits in the distal appendage hierarchy and its downstream effector resolved a key gap in understanding centriolar appendage assembly: LRRC45 is recruited by CEP83–SCLT1 and in turn recruits FBF1.

   Evidence Genetic epistasis via sequential knockdowns with co-localization in cultured cells

   PMID:30131441

   Open questions at the time

   • Direct biochemical interaction between LRRC45 and SCLT1/CEP83 not demonstrated
   • Structural basis of LRRC45–FBF1 interaction unknown
2. 2018 High

   Defining the specific ciliogenesis steps controlled by LRRC45 established that it acts after CP110 removal to organize satellites, build the transition zone, and dock Rab8 vesicles, rather than initiating ciliary vesicle capture.

   Evidence Multi-readout loss-of-function assays (transition zone markers, Rab8 vesicle docking, CP110 status) in differentiated and stem cells

   PMID:30131441

   Open questions at the time

   • Mechanism by which LRRC45 organizes centriolar satellites is unknown
   • Whether LRRC45 directly interacts with Rab8 or acts indirectly not resolved
3. 2018 Medium

   Identifying LRRC45 as a physical interactor of CCDC102B within the centrosome linker revealed a second, spatially distinct function at proximal centrioles maintaining centrosome cohesion.

   Evidence Co-immunoprecipitation and centrosome cohesion knockdown assays in human cells

   PMID:30404835

   Open questions at the time

   • LRRC45–CCDC102B interaction not validated by reciprocal pull-down or in vitro reconstitution
   • How LRRC45 integrates with rootletin filaments structurally is unknown
4. 2020 Medium

   Showing that LRRC45 centrosome linker localization is independent of Cep44 delineated LRRC45 as part of a separately assembled linker module, clarifying the modularity of centrosome architecture.

   Evidence Depletion of Cep44 with immunofluorescence and western blot in human cells

   PMID:31974111

   Open questions at the time

   • Identity of the factor that recruits LRRC45 to the linker remains unresolved
   • Functional consequence of LRRC45 linker loss on centriole separation timing not measured
5. 2024 Medium

   Discovery that biallelic LRRC45 loss-of-function variants in patients cause reduced cilia frequency and length translated cell-biological findings into human disease, establishing LRRC45 as a ciliopathy gene.

   Evidence Exome sequencing, RT-PCR for aberrant splicing, western blot, and cilia quantification in patient-derived fibroblasts

   PMID:39638757

   Open questions at the time

   • Clinical spectrum of LRRC45-associated ciliopathy not fully defined
   • Rescue of patient cells with wild-type LRRC45 not reported
   • Only a single family reported
6. 2024 Medium

   Demonstrating that LRRC45 competitively binds KEAP1 to stabilize NRF2 and inhibit ferroptosis revealed an unexpected non-centrosomal signaling role in bladder cancer cells.

   Evidence Co-IP, competitive binding assays, ubiquitination assays, and nuclear fractionation in bladder cancer cell lines

   PMID:39522565

   Open questions at the time

   • Whether LRRC45–KEAP1 interaction occurs in non-cancer contexts is unknown
   • ETGE/DLG-like motif in LRRC45 mediating KEAP1 binding not mapped
   • Independent replication in additional cell types not reported
7. 2024 Medium

   Placing LRRC45 upstream of c-MYC, Slug, MMP2, and MMP9 in lung adenocarcinoma provided an epistatic framework for its pro-proliferative and pro-metastatic activity in cancer.

   Evidence siRNA knockdown and rescue overexpression with colony formation, migration assays, and xenograft models

   PMID:39326735

   Open questions at the time

   • Direct molecular link between LRRC45 and c-MYC/Slug transcription not identified
   • Whether these cancer phenotypes relate to centrosome or cilia function is unclear
   • Single lab study without independent validation
8. 2025 High

   Comprehensive CRISPR knockout with super-resolution imaging confirmed and refined LRRC45 placement within the distal appendage assembly hierarchy downstream of CEP83–SCLT1 and the CEP164–TTBK2 module.

   Evidence CRISPR-Cas9 knockout panel with super-resolution localization and ciliogenesis assays

   PMID:39882846

   Open questions at the time

   • Precise sub-appendage nanoscale position of LRRC45 relative to FBF1 not fully resolved
   • Direct interactions within the distal appendage assembly not reconstituted biochemically

• The structural basis of LRRC45 interactions at both the centrosome linker and distal appendages, the molecular mechanism connecting LRRC45 to satellite organization and transition zone assembly, and the relationship between its centrosomal and non-centrosomal (KEAP1/NRF2) functions remain unresolved.
• No crystal or cryo-EM structure of LRRC45 or its complexes
• Mechanism of satellite organization by LRRC45 unknown
• Whether centrosomal and KEAP1-related functions are context-dependent or coexistent is untested