ARL3, a small GTPase with a functionally conserved role in primary cilia and immune synapses

Powell, Laura; Samarakoon, Youhani; Ismail, Shehab; Sayer, John A.

doi:10.1080/21541248.2019.1703466

Cited by 13 publications

(16 citation statements)

References 85 publications

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“…All three of these genes participate in the targeting and delivery of lipidated proteins to cilia membranes. Unc119 (Unc-119 lipid binding chaperone B) is a myristoyl-binding protein that acts as a cargo adapter for lipidated protein transport, Arl3 (ADP-ribosylation factor-like 3) is a small GTPase involved in the targeting and releasing of lipidated cargo proteins from their carriers at the cilium ( Powell et al, 2019 ; Zhou et al, 2006 ), and Arl13b (ADP ribosylation factor-like GTPase 13b) is the guanine nucleotide exchange factor that activates Arl3 ( Duldulao et al, 2009 ; Gotthardt et al, 2015 ; Nozaki et al, 2017 ). We confirmed that upregulation of arl3 , arl13b and unc119b assayed in larvae also occurred in MZcep290 −/− adult eye samples ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Currently, the mechanism for this compensation is unknown but it is significant that the compensating genes function in a subcellular pathway central to Cep290 activity ( Craige et al, 2010 ; Drivas et al, 2013 ; McEwen et al, 2007 ; Tsang et al, 2008 ). Arl3 and Arl13b are small GTPases that interact with the adaptor protein Unc119b to mediate cilia lipidated membrane protein transport ( Alkanderi et al, 2018 ; Duldulao et al, 2009 ; Gotthardt et al, 2015 ; Nozaki et al, 2017 ; Powell et al, 2019 ). Unc119b also interacts with the NPHP-MKS protein complex, which is involved in ciliary gate function at the cilia transition zone and interacts with CEP290 through NPHP5 ( Sang et al, 2011 ; Schäfer et al, 2008 ; Williams et al, 2011 ; Wright et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…(ADP-ribosylation factor-like 3), is a small GTPase involved in targeting and releasing of lipidated cargo proteins from their carriers at the cilium (Powell et al, 2019;Zhou et al, 2006), and Arl13b (ADP ribosylation factor like GTPase 13B) is the guanine nucleotide exchange factor (GEF) that activates Arl3 (Duldulao et al, 2009;Gotthardt et al, 2015;Nozaki et al, 2017). We confirmed that upregulation of arl3, arl13b and unc119b assayed in larvae also occurred in Journal of Cell Science • Accepted manuscript MZcep290-/-adult eye samples (Fig 5C ) but not in cep290ex25 morphants or cep290-/-zygotic mutant embryos which displayed prominent axis curvature (Fig 5D,E).…”

Section: Genetic Mutation In Zebrafish Cep290 Induces Upregulation Of Genes Encoding Cep290 Interactors Involved In Cilia Membrane Transpmentioning

confidence: 99%

“…GTPases that interact with the adaptor protein Unc119b to mediate cilia lipidated membrane protein transport (Alkanderi et al, 2018;Duldulao et al, 2009;Gotthardt et al, 2015;Nozaki et al, 2017;Powell et al, 2019). Unc119b also interacts with the NPHP-MKS protein complex which is involved in ciliary gate function at the cilia transition zone and interacts with CEP290…”

Section: Genetic Compensation Including Transcriptional Adaptation In Genetic Mutants Has Beenmentioning

confidence: 99%

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Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Cárdenas-Rodríguez

Austin‐Tse

Bergboer

et al. 2021

Journal of Cell Science

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Mutations in CEP290, a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes while defects in a Crispr/Cas9 genetic mutant were restricted to photoreceptor defects. Here we show that milder phenotypes in genetic mutants were associated with upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b, and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human JBTS CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Genetic Mutation In Zebrafish Cep290 Induces Upregulation Of Genes Encoding Cep290 Interactors Involved In Cilia Membrane Transpmentioning

confidence: 99%

Section: Genetic Compensation Including Transcriptional Adaptation In Genetic Mutants Has Beenmentioning

confidence: 99%

See 2 more Smart Citations

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Cárdenas-Rodríguez

Austin‐Tse

Bergboer

et al. 2021

Journal of Cell Science

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“…We did however find a decrease in expression of arl3l2 . ARL3 proteins are present in the cilia and mutations lead to Joubert syndrome in humans (Alkanderi et al, 2018; Powell et al, 2019). Whether arl3l2 plays a role in cilia activity in the zebrafish is currently unknown but may provide a mechanistic link between hnrnpul1/1l and scoliosis.…”

Section: Discussionmentioning

confidence: 99%

Hnrnpul1 controls transcription, splicing, and modulates skeletal and limb development in vivo

Blackwell

Fraser

Caluseriu

et al. 2020

Preprint

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180 words) 3 2 Mutations in RNA binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, 3 3 limb and neurological symptoms. Heterogeneous Nuclear Ribonucleoproteins (hnRNPs) are involved 3 4in nucleic acid binding, transcription and splicing through direct binding to DNA and RNA, or through 3 5interaction with other proteins in the spliceosome. Here, we show a developmental role for hnrnpul1 in 3 6zebrafish fin and craniofacial development, and in adult onset scoliosis. Furthermore, we demonstrate 3 7 a role of hnrnpul1 in alternative splicing regulation. In two siblings with congenital limb malformations, 3 8whole exome sequencing detected a frameshift variant in HNRNPUL1; the developmental role of this 3 9gene in humans has not been explored. Our data suggest an important developmental role of 4 0 hnRNPUL1 in both zebrafish and humans. Although there are differences in phenotypes between 4 1 species, our data suggests potential conservation of ancient regulatory circuits involving hnRNPUL1 in 4 2 these phylogenetically distant species. 4 3

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BAG3 regulates cilia homeostasis of glioblastoma via its WW domain

Roth,

Paulini,

Hoffmann

et al. 2024

BioFactors

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The multidomain protein BAG3 exerts pleiotropic oncogenic functions in many tumor entities including glioblastoma (GBM). Here, we compared BAG3 protein–protein interactions in either adherently cultured or stem‐like cultured U251 GBM cells. In line with BAG3's putative role in regulating stem‐like properties, identified interactors in sphere‐cultured cells included different stem cell markers (SOX2, OLIG2, and NES), while interactomes of adherent BAG3‐proficient cells indicated a shift toward involvement of BAG3 in regulation of cilium assembly (ACTR3 and ARL3). Applying a set of BAG3 deletion constructs we could demonstrate that none of the domains except the WW domain are required for suppression of cilia formation by full‐length BAG3 in U251 and U343 cells. In line with the established regulation of the Hippo pathway by this domain, we could show that the WW mutant fails to rescue YAP1 nuclear translocation. BAG3 depletion reduced activation of a YAP1/AURKA signaling pathway and induction of PLK1. Collectively, our findings point to a complex interaction network of BAG3 with several pathways regulating cilia homeostasis, involving processes related to ciliogenesis and cilium degradation.

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ARL3, a small GTPase with a functionally conserved role in primary cilia and immune synapses

Cited by 13 publications

References 85 publications

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Hnrnpul1 controls transcription, splicing, and modulates skeletal and limb development in vivo

BAG3 regulates cilia homeostasis of glioblastoma via its WW domain

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