Differential role of Rab proteins in ciliary trafficking: Rab23 regulates Smoothened levels

Boehlke, Christopher; Bashkurov, Mikhail; Buescher, Andrea; Krick, Theda; John, Anne-Katharina; Nitschke, Roland; Walz, Gerd; Kuehn, E. Wolfgang

doi:10.1242/jcs.058883

Cited by 99 publications

(91 citation statements)

References 36 publications

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“…20,23,24,26 Consistently, silencing of PI3K-C2a in collecting-duct derived IMCD3 cells impaired Rab11 activation in a dose-dependent manner and prevented the ciliary localization of Rab8. This Rab GTPase represents a key hub regulating selective entry of proteins inside the ciliary compartment 21,32,37 and delivery of material required for cilium elongation. 23 In agreement, silencing of PI3K-C2a in IMCD3 cells resulted in impaired targeting of polycystin-2 and reduced cilium length.…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

Franco

Margaria

Santis

et al. 2016

Journal of the American Society of Nephrology

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Signaling from the primary cilium regulates kidney tubule development and cyst formation. However, the mechanism controlling targeting of ciliary components necessary for cilium morphogenesis and signaling is largely unknown. Here, we studied the function of class II phosphoinositide 3-kinase-C2a (PI3K-C2a) in renal tubule-derived inner medullary collecting duct 3 cells and show that PI3K-C2a resides at the recycling endosome compartment in proximity to the primary cilium base. In this subcellular location, PI3K-C2a controlled the activation of Rab8, a key mediator of cargo protein targeting to the primary cilium. Consistently, partial reduction of PI3K-C2a was sufficient to impair elongation of the cilium and the ciliary transport of polycystin-2, as well as to alter proliferation signals linked to polycystin activity. In agreement, heterozygous deletion of PI3K-C2a in mice induced cilium elongation defects in kidney tubules and predisposed animals to cyst development, either in genetic models of polycystin-1/2 reduction or in response to ischemia/reperfusion-induced renal damage. These results indicate that PI3K-C2a is required for the transport of ciliary components such as polycystin-2, and partial loss of this enzyme is sufficient to exacerbate the pathogenesis of cystic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

Franco

Margaria

Santis

et al. 2016

Journal of the American Society of Nephrology

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“…Of note, VAMP-3 also regulates Smo trafficking to the cilium. Vesicular trafficking is centrally implicated in the dynamic ciliary localization of this receptor, on which Hedgehog signaling crucially depends, as underscored by the variety of Rab and Arl GTPases that are required for the ciliary targeting of Smo, including Rab8, Rab23 and Arl6 (Boehlke et al, 2010;Zhang et al, 2011). VAMP-3 is the first SNARE to be identified in this pathway.…”

Section: Discussionmentioning

confidence: 99%

The small GTPase Rab8 interacts with VAMP-3 to regulate the delivery of recycling TCRs to the immune synapse

Finetti

Patrussi

Galgano

et al. 2015

Journal of Cell Science

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IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, regulates immune synapse assembly in the non-ciliated T-cell by promoting T-cell receptor (TCR) recycling. Here, we have addressed the role of Rab8 (for which there are two isoforms Rab8a and Rab8b), a small GTPase implicated in ciliogenesis, in TCR traffic to the immune synapse. We show that Rab8, which colocalizes with IFT20 in Rab11 + endosomes, is required for TCR recycling. Interestingly, as opposed to in IFT20-deficient T-cells, TCR + endosomes polarized normally beneath the immune synapse membrane in the presence of dominant-negative Rab8, but were unable to undergo the final docking or fusion step. This could be accounted for by the inability of the vesicular (v)-SNARE VAMP-3 to cluster at the immune synapse in the absence of functional Rab8, which is responsible for its recruitment. Of note, and similar to in T-cells, VAMP-3 interacts with Rab8 at the base of the cilium in NIH-3T3 cells, where it regulates ciliary growth and targeting of the protein smoothened. The results identify Rab8 as a new player in vesicular traffic to the immune synapse and provide insight into the pathways co-opted by different cell types for immune synapse assembly and ciliogenesis.

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“…Zebrafish Kif7 potentiates the activity of Gli2 by promoting its dissociation from Sufu (Maurya et al, 2013). It is also known that Rab23, which regulates endocytic and ciliary trafficking (Evans et al, 2003;Boehlke et al, 2010), is highly expressed in the dorsal neural tube and regulates Hh signaling during neural tube patterning (Eggenschwiler et al, 2001;Li et al, 2007). Similar to Rusc proteins, Rab23 functions downstream of Smo and Ptch and inhibits Gli1 in a Sufu-dependent manner (Evans et al, 2003;Eggenschwiler et al, 2006;Chi et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

Jin¹,

Schwend²,

Fu³

et al. 2016

Journal of Cell Science

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Hedgehog (Hh) signaling is fundamentally important for development and adult tissue homeostasis. It is well established that in vertebrates Sufu directly binds and inhibits Gli proteins, the downstream mediators of Hh signaling. However, it is unclear how the inhibitory function of Sufu towards Gli is regulated. Here we report that the Rusc family of proteins, the biological functions of which are poorly understood, form a heterotrimeric complex with Sufu and Gli. Upon Hh signaling, Rusc is displaced from this complex, followed by dissociation of Gli from Sufu. In mammalian fibroblast cells, knockdown of Rusc2 potentiates Hh signaling by accelerating signaling-induced dissociation of the Sufu-Gli protein complexes. In Xenopus embryos, knockdown of Rusc1 or overexpression of a dominant-negative Rusc enhances Hh signaling during eye development, leading to severe eye defects. Our study thus uncovers a novel regulatory mechanism controlling the response of cells to Hh signaling in vertebrates.

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Differential role of Rab proteins in ciliary trafficking: Rab23 regulates Smoothened levels

Cited by 99 publications

References 36 publications

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

The small GTPase Rab8 interacts with VAMP-3 to regulate the delivery of recycling TCRs to the immune synapse

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

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