The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

Turn, Rachel E; Hu, Yihan; Dewees, Skylar I; Devi, Narra S.; East, Michael P.; Hardin, Katherine R; Khatib, Tala O.; Linnert, Joshua; Wolfrum, Uwe; Lim, Michael J.; Casanova, James E.; Caspary, Tamara; Kahn, Richard

doi:10.1091/mbc.e21-09-0443_corr

Cited by 8 publications

(14 citation statements)

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“…The ELMODs are ancient proteins in diverse eukaryotes. ELMOs are predicted to originate from the ELMODs [3,5,6]. ELMO domain is a common feature linking ELMOs and ELMODs proteins.…”

Section: Introductionmentioning

confidence: 99%

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

et al. 2023

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Lumen development is a crucial phase in tubulogenesis, although its molecular mechanisms are largely unknown. In this study, we discovered an ELMO domain-containing 3 (ELMOD3), which belongs to ADP-ribosylation factor GTPase-activating protein family, was necessary to form the notochord lumen in Ciona larvae . We demonstrated that ELMOD3 interacted with lipid raft protein Flotillin2 and regulated its subcellular localization. The loss-of-function of Flotillin2 prevented notochord lumen formation. Furthermore, we found that ELMOD3 also interacted with Rab1A, which is the regulatory GTPase for vesicle trafficking and located at the notochord cell surface. Rab1A mutations arrested the lumen formation, phenocopying the loss-of-function of ELMOD3 and Flotillin2. Our findings further suggested that Rab1A interactions influenced Flotillin2 localization. We thus identified a unique pathway in which ELMOD3 interacted with Rab1A, which controlled the Flotillin2-mediated vesicle trafficking from cytoplasm to apical membrane, required for Ciona notochord lumen formation.

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“…The ELMODs are ancient proteins in diverse eukaryotes. ELMOs are predicted to originate from the ELMODs [3,5,6]. ELMO domain is a common feature linking ELMOs and ELMODs proteins.…”

Section: Introductionmentioning

confidence: 99%

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

et al. 2023

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“…The downstream targets for MAPK15 in ciliogenesis beyond ELMOD are currently unclear. While previous work has linked both MAPK15 and ELMOD to ciliary trafficking (Cevik et al, 2021;Kazatskaya et al, 2017;Turn et al, 2022;Turn et al, 2021), this clearly cannot explain their role in IFT-independent cilium biogenesis in Drosophila sperm and (in the case of MAPK15) Plasmodium. It is also notable that no other C. elegans gene to date shares their dual phenotype in transition zone assembly and axoneme extension.…”

Section: Discussionmentioning

confidence: 80%

“…In contrast, ELMOD family members are thought to act as ARF/ARL GAPs, with broad cellular effects, including on the actin cytoskeleton (Li et al, 2019b). All three vertebrate ELMOD proteins have recently been localized to basal bodies and linked to ciliogenesis, albeit with seemingly opposing effects: While loss of ELMOD1 and 3 reduced ciliation in mouse embryonic fibroblasts, loss of ELMOD2 actually resulted in an increase, with those cilia displaying abnormal morphology, including apparent splaying of axonemes and ciliary rootlet defects (Turn et al, 2022;Turn et al, 2021) (ultrastructural analysis has so far not been performed). Common to all three perturbations is a mislocalization of ciliary proteins, suggesting ciliary trafficking is at least partly responsible for the observed defects (Turn et al, 2022;Turn et al, 2021).…”

Section: Mapk15 and Elmod As Highly Conserved Regulators Of Ciliogenesismentioning

confidence: 99%

A Phylogenetic Profiling Approach Identifies Novel Ciliogenesis Genes InDrosophilaAndC. elegans

Dobbelaere

Érdi

et al. 2022

Preprint

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Cilia are cellular projections that perform sensory and motile functions in eukaryotic cells. A defining feature of cilia is that they are evolutionarily ancient yet not universally conserved. In this study we have used the resulting presence and absence pattern in the genomes of diverse eukaryotes to identify a set of 386 human genes associated with cilium assembly or motility. Comprehensive tissue-specific RNAi in Drosophila and mutant analysis in C. elegans revealed signature ciliary defects for 70-80% of novel genes, a percentage similar to that for known genes within the cluster. Further characterization identified different phenotypic classes, including a set of genes related to the cartwheel component Bld10/Cep135 and two highly conserved regulators of cilium biogenesis. We believe this dataset to define the core set of genes required for cilium assembly and motility across eukaryotes, an invaluable resource for future studies of cilium biology and associated disorders.

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“…Amongst those, we observed downregulation of Dcdc2, encoding for a protein containing 2 doublecortin peptide domains, localizing to primary 13 cilia and playing a role in tubulin binding, microtubule polymerization and Wnt signaling regulation (Schueler et al, 2015). We further found that several differentially downregulated genes encode for Golgi-associated proteins and proteins involved in vesicle trafficking, including Rab6b (Wanschers et al, 2007), the ARF GAP Elmod1 (Turn et al, 2021) which has very recently also linked to protein transport from the Golgi to the cilium (Turn et al, 2021), Myo5c (Sladewski et al, 2016) and Zdhhc14 (Sanders et al, 2020) (Figure 5G and H). While GO term analyses did not reveal enrichment of G-protein-coupled receptor signaling, we detected upregulation of two Gprotein signaling pathway associated genes Rgs2 and Snca.…”

Section: Wdr34 and Wdr60 Human Disease Alleles Influence Gene Transcr...mentioning

confidence: 78%

“…In line with impaired Golgi protein transport functions under stress, we observed reduced expression of several other Golgi-associated proteins including ELMOD1 in all dynein-2 mutants (both ciliated and non-ciliated cells) compared to controls. The GTPase activating protein ELMOD1 is a GTPase activating protein that acts mainly on ADP-ribosylation factor (ARF) family GTPases and knockout affects primary cilia formation, reducing ciliary ARL13B expression and resulting in accumulation of INPP5E and IFT140 at the Golgi (Turn et al, 2021). Knockout mice present with fused and elongated stereocilia in the inner ear and disturbed intracellular vesicle trafficking in knockout cells has been described (Krey et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Base editing derived models of human WDR34 and WDR60 disease alleles replicate retrograde IFT and hedgehog signaling defects and suggest disturbed Golgi protein transport

Antony

Güleç²,

Bakey³

et al. 2022

Preprint

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Cytoplasmic Dynein-2 / IFT-dynein is the only known retrograde motor for intraflagellar transport. Dysfunction of WDR34 and WDR60, the two intermediate chains of this complex, causes Short Rib Thoracic Dystrophy (SRTD), human skeletal chondrodysplasias with high lethality. Complete loss of function of WDR34 or WDR60 is lethal in vertebrates and individuals with SRTD carry at least one putative hypomorphic missense allele. Gene knockout is therefore not suitable to study the effect of these human missense disease alleles. Using CRISPR single base editors, we recreated three different patient missense alleles.Consistent with previous findings in the dynein-2 full loss of function models and patient fibroblasts, mutant cell lines showed hedgehog signaling defects as well as disturbed retrograde IFT. Transcriptomics analyses revealed differentially regulated expression of genes associated with various biological processes, including regulation of the actin cytoskeleton. Further, we observed differential regulation of genes associated with Golgi intracellular transport. In addition to providing cellular model systems enabling investigations of the effect of human SRTD disease alleles, our findings indicate non-ciliary functions for WDR34 and WDR60 in addition to the established roles as components of the retrograde IFT motor complex in cilia.

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The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

Cited by 8 publications

References 0 publications

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

A Phylogenetic Profiling Approach Identifies Novel Ciliogenesis Genes InDrosophilaAndC. elegans

Base editing derived models of human WDR34 and WDR60 disease alleles replicate retrograde IFT and hedgehog signaling defects and suggest disturbed Golgi protein transport

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