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Tamara Caspary – 1st expert on this subject based on the ideXlab platform
ARF Family GTPases with Links to Cilia.American journal of physiology. Cell physiology, 2020Co-Authors: Skylar Fisher, Richard A Kahn, Tamara Caspary, Damian Kuna, Elizabeth SztulAbstract:
The ARF superfamily of regulatory GTPases, including both the ARF and ARL proteins, control a multitude of cellular functions including aspects of vesicular traffic, lipid metabolism, mitochondrial architecture, the assembly and dynamics of the microtubule and actin cytoskeletons, and other pathways in cell biology. Considering their general utility, it is perhaps not surprising that increasingly ARF/ARLs have been found in connection to primary cilia. Here, we critically evaluate the current knowledge of the role four ARF/ARLs (ARF4, ARL3, ARL13B and ARL6) play in cilia and highlight key missing information that would help move our understanding forward. Importantly, these GTPases are themselves regulated by guanine nucleotide exchange factors (GEFs) that activate them and by GTPase activating proteins (GAPs) that act as both effectors and terminators of signaling. We believe that the identification of the GEFs and GAPs and better models of the actions of these GTPases and their regulators will provide a much deeper understanding and appreciation of the mechanisms that underly ciliary functions and the causes of a number of human ciliopathies.
ARL13B regulates sonic hedgehog signaling from outside primary ciliaeLife, 2020Co-Authors: Eduardo D Gigante, Richard A Kahn, Anna A. Ivanova, Megan R Taylor, Tamara CasparyAbstract:
: ARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of ARL13B disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To determine whether ARL13B is required within cilia, we knocked in a cilia-excluded variant of ARL13B (V358A) and showed it retains all known biochemical function. We found that ARL13BV358A protein was expressed but could not be detected in cilia, even when retrograde ciliary transport was blocked. We showed ARL13BV358A/V358A mice are viable and fertile with normal Shh signal transduction. However, in contrast to wild type cilia, ARL13BV358A/V358A cells displayed short cilia and lacked ciliary ARL3 and INPP5E. These data indicate that ARL13B‘s role within cilia can be uncoupled from its function outside of cilia. Furthermore, these data imply that the cilia defects upon complete absence of ARL13B do not underlie the alterations in Shh transduction, which is unexpected given the requirement of cilia for Shh transduction.
the ciliary protein ARL13B functions outside of the primary cilium in shh mediated axon guidanceCell Reports, 2019Co-Authors: Julien Ferent, Karel F Liem, Tamara Caspary, Laura E Mariani, Sandii Constable, Eduardo D Gigante, Emilie Legue, Frederic CharronAbstract:
Summary The small GTPase ARL13B is enriched in primary cilia and regulates Sonic hedgehog (Shh) signaling. During neural development, Shh controls patterning and proliferation through a canonical, transcription-dependent pathway that requires the primary cilium. Additionally, Shh controls axon guidance through a non-canonical, transcription-independent pathway whose connection to the primary cilium is unknown. Here we show that inactivation of ARL13B results in defective commissural axon guidance in vivo. In vitro, we demonstrate that ARL13B functions autonomously in neurons for their Shh-dependent guidance response. We detect ARL13B protein in axons and growth cones, far from its well-established ciliary enrichment. To test whether ARL13B plays a non-ciliary function, we used an engineered, cilia-localization-deficient ARL13B variant and found that it was sufficient to mediate Shh axon guidance in vitro and in vivo. Together, these results indicate that, in addition to its ciliary role in canonical Shh signaling, ARL13B plays a cilia-independent role in Shh-mediated axon guidance.
Jinghua Hu – 2nd expert on this subject based on the ideXlab platform
axoneme polyglutamylation regulated by joubert syndrome protein ARL13B controls ciliary targeting of signaling moleculesNature Communications, 2018Co-Authors: Kai He, Tao Xu, Yan Li, Allen Hodge, Qing Zhang, Julia Torline, Yan Huang, Jian Zhao, Kun Ling, Jinghua HuAbstract:
Tubulin polyglutamylation is a predominant axonemal post-translational modification. However, if and how axoneme polyglutamylation is essential for primary cilia and contribute to ciliopathies are unknown. Here, we report that Joubert syndrome protein ARL13B controls axoneme polyglutamylation, which is marginally required for cilia stability but essential for cilia signaling. ARL13B interacts with RAB11 effector FIP5 to promote cilia import of glutamylase TTLL5 and TTLL6. Hypoglutamylation caused by a deficient ARL13B-RAB11-FIP5 trafficking pathway shows no effect on ciliogenesis, but promotes cilia disassembly and, importantly, impairs cilia signaling by disrupting the proper anchoring of sensory receptors and trafficking of signaling molecules. Remarkably, depletion of deglutamylase CCP5, the predominant cilia deglutamylase, effectively restores hypoglutamylation-induced cilia defects. Our study reveals a paradigm that tubulin polyglutamylation is a major contributor for cilia signaling and suggests a potential therapeutic strategy by targeting polyglutamylation machinery to promote ciliary targeting of signaling machineries and correct signaling defects in ciliopathies.
Molecular views of Arf-like small GTPases in cilia and ciliopathiesExperimental Cell Research, 2013Co-Authors: Qing Zhang, Jinghua Hu, Kun LingAbstract:
Abstract The primary cilia are microtubule-based organelles that protrude from most of the eukaryotic cells. Recognized as the cell’s antenna, primary cilium functions as a signaling hub for many physiologically and developmentally important signaling cascades. Ciliary dysfunction causes a wide spectrum of syndromic human genetic diseases collectively termed “ciliopathies”. Mounting evidences have shown that various small GTPases have been implicated in the context of cilia as well as human ciliopathies. However, how these small GTPases affect cilia formation and function remains poorly understood. Here we review and discuss the ciliary role of three Arf-like small GTPases (Arls), Arl3, Arl6, and ARL13B.
SUMOylation of the small GTPase ARL-13 promotes ciliary targeting of sensory receptors.Journal of Cell Biology, 2013Co-Authors: Yujie Li, Kun Ling, Qing Zhang, Yuxia Zhang, Jinghua HuAbstract:
Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13–null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.
Cynthia Y He – 3rd expert on this subject based on the ideXlab platform
flagellar targeting of an arginine kinase requires a conserved lipidated protein intraflagellar transport lift pathway in trypanosoma bruceiJournal of Biological Chemistry, 2020Co-Authors: Maneesha Pandey, Yameng Huang, Cynthia Y HeAbstract:
Both intraflagellar transport (IFT) and lipidated protein intraflagellar transport (LIFT) pathways are essential for cilia/flagella biogenesis, motility, and sensory functions. In the LIFT pathway, lipidated cargoes are transported into the cilia through the coordinated actions of cargo carrier proteins such as Unc119 or PDE6δ, as well as small GTPases ARL13B and Arl3 in the cilium. Our previous studies have revealed a single ARL13B ortholog in the evolutionarily divergent Trypanosoma brucei, the causative agent of African sleeping sickness. TbArl13 catalyzes two TbArl3 homologs, TbArl3A and TbArl3C, suggesting the presence of a conserved LIFT pathway in these protozoan parasites. Only a single homolog to the cargo carrier protein Unc119 has been identified in T. brucei genome, but its function in lipidated protein transport has not been characterized. In this study, we exploited the proximity-based biotinylation approach to identify binding partners of TbUnc119. We showed that TbUnc119 binds to a flagellar arginine kinase TbAK3 in a myristoylation-dependent manner and is responsible for its targeting to and enrichment in the flagellum. Interestingly, only TbArl3A, but not TbArl3C interacted with TbUnc119 in a GTP-dependent manner, suggesting functional specialization of Arl3-GTPases in T. brucei These results establish the function of TbUnc119 as a myristoylated cargo carrier and support the presence of a conserved LIFT pathway in T. brucei.
Flagellar targeting of an arginine kinase requires the conserved Lipidated Intraflagellar Transport (LIFT) pathway in Trypanosoma bruceibioRxiv, 2020Co-Authors: Maneesha Pandey, Yameng Huang, Cynthia Y HeAbstract:
Both intraflagellar transport (IFT) and lipidated intraflagellar transport (LIFT) pathways are essential for cilia/flagella biogenesis, motility and sensory functions. In the LIFT pathway, lipidated cargoes are transported into the cilia through the coordinated actions of cargo carrier proteins such as Unc119 or PDE6δ, as well as small GTPases ARL13B and Arl3 in the cilium. Our previous studies revealed a single ARL13B ortholog in the evolutionarily divergent Trypanosoma brucei. TbArl13 catalyses two TbArl3 homologs, TbArl3A and TbArl3C, suggesting the presence of a conserved LIFT pathway in these protozoan parasites. Only a single homolog to the cargo carrier protein Unc119 was identified in T. brucei genome, but its function in lipidated protein transport has not been characterized. In this study, we exploited the proximity-based biotinylation approach to identify binding partners of TbUnc119. We showed that TbUnc119 binds to a flagellar arginine kinase TbAK3 in a myristoylation-dependent manner and is responsible for its targeting and enrichment in the flagellum. Interestingly, only TbArl3A, but not TbArl3C interacts with TbUnc119 in a GTP-dependant manner, suggesting functional specialization of Arl3-GTPases in T. brucei. This study establishes the function of TbUnc119 as a myristoylated cargo carrier and supports the presence of a conserved LIFT pathway in T. brucei.
the unusual flagellar targeting mechanism and functions of the trypanosome ortholog of the ciliary gtpase ARL13BJournal of Cell Science, 2018Co-Authors: Yiliu Zhang, Yameng Huang, Amrita Srivathsan, Cynthia Y HeAbstract:
The small GTPase ARL13B is one of the most conserved and ancient ciliary proteins. In human and animals, ARL13B is primarily associated with the ciliary membrane, where it acts as a Guanine-nucleotide Exchange Factor (GEF) for Arl3 and is implicated in a variety of ciliary and cellular functions. We have identified and characterized TbArl13, the sole ARL13B homologue in the evolutionarily divergent, protozoan parasite Trypanosoma brucei. TbArl13 has conserved flagellar functions and exhibits catalytic activity towards two different TbArl3 homologues. However, TbArl13 is distinctly associated with the axoneme through a dimerization/docking (D/D) domain. Replacing the D/D domain with a flagellar membrane protein created a viable alternative to the wild-type TbArl13 in our RNA interference (RNAi)-based rescue assay. Therefore, flagellar enrichment is crucial for TbArl13 but mechanisms to achieve this could be flexible. Our findings thus extended the understanding of ARL13B and ARL13B-Arl3 pathway in a divergent flagellate of medical importance.