Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADP-ribosylation factor 4 (ARF4)

Deretic, Dusanka; Williams, Andrew H; Ransom, Nancy; Morel, Valérie; Hargrave, Paul A.; Arendt, Anatol

doi:10.1073/pnas.0500095102

Cited by 183 publications

(202 citation statements)

References 41 publications

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“…We focused primarily on the C termini of these proteins since both the hydrophobic/ basic and VxPx CTSs are present in this region in other GPCRs, and sequences in this domain have been shown to be both necessary and sufficient to direct GPCRs to cilia (Deretic et al 1998(Deretic et al , 2005Corbit et al 2005;Wang et al 2012;.…”

Section: Resultsmentioning

confidence: 99%

“…Intriguingly, although the FR ciliary targeting motif in rhodopsin interacts directly with the ASAP1 Arf4 GAP protein , the C. elegans genome does not encode an ASAP1 ortholog, implying that this motif may also be recognized by alternate ciliary trafficking mechanisms. In addition to the hydrophobic/basic residue, the C terminus of rhodopsin also contains a VxPx motif required for localization to the photoreceptor outer segment via interaction with the Arf GTPase (Deretic et al 1998(Deretic et al , 2005Wang et al 2012). A VxPx motif was identified in the C terminus of SRD-23 ( Figure 2A); however, mutating this motif did not affect SRD-23 localization to the AWB cilia (Table 2).…”

Section: Mechanisms Of Gpcr Ciliary Localization 671mentioning

confidence: 99%

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Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

Brear

Yoon

Wojtyniak³

et al. 2014

Genetics

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The localization of signaling molecules such as G protein-coupled receptors (GPCRs) to primary cilia is essential for correct signal transduction. Detailed studies over the past decade have begun to elucidate the diverse sequences and trafficking mechanisms that sort and transport GPCRs to the ciliary compartment. However, a systematic analysis of the pathways required for ciliary targeting of multiple GPCRs in different cell types in vivo has not been reported. Here we describe the sequences and proteins required to localize GPCRs to the cilia of the AWB and ASK sensory neuron types in Caenorhabditis elegans. We find that GPCRs expressed in AWB or ASK utilize conserved and novel sequences for ciliary localization, and that the requirement for a ciliary targeting sequence in a given GPCR is different in different neuron types. Consistent with the presence of multiple ciliary targeting sequences, we identify diverse proteins required for ciliary localization of individual GPCRs in AWB and ASK. In particular, we show that the TUB-1 Tubby protein is required for ciliary localization of a subset of GPCRs, implying that defects in GPCR localization may be causal to the metabolic phenotypes of tub-1 mutants. Together, our results describe a remarkable complexity of mechanisms that act in a protein-and cellspecific manner to localize GPCRs to cilia, and suggest that this diversity allows for precise regulation of GPCR-mediated signaling as a function of external and internal context. SIGNALING molecules must be precisely localized to specific subcellular domains to optimize detection and transduction of external stimuli. G protein-coupled receptors (GPCRs) comprise a large family of transmembrane signaling proteins that directly bind and transduce a range of cues including photons, odorants, neurotransmitters, and peptides (Pierce et al. 2002;Kato and Touhara 2009;Demaria and Ngai 2010;Sung and Chuang 2010;Chamero et al. 2012;Frooninckx et al. 2012;Montell 2012;Bathgate et al. 2013). Regulation of GPCR function, including regulation of membrane targeting and trafficking to specific subcellular regions, is a major contributor to the tuning of signaling efficacy and fidelity (e.g., Deretic et al. 1995;Ango et al. 2000;Xia et al. 2003;Esseltine et al. 2012;. However, much remains to be understood regarding the mechanisms by which GPCR trafficking and membrane localization are regulated.GPCR-mediated signal transduction in many cellular contexts requires these proteins to be localized to specialized microtubule-based primary cilia. For example, in photoreceptors and olfactory neurons, efficient sensory signal transduction is mediated via localization of rhodopsin and olfactory receptors, together with other signaling molecules, to photoreceptor outer segments and olfactory neuron cilia, respectively (Insinna and Besharse 2008;Berbari et al. 2009;Pifferi et al. 2010;Deretic and Wang 2012). Receptors in the Hedgehog (Hh) morphogen signaling pathway such as the Smoothened and Patched transmembrane proteins, and the G...

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Section: Resultsmentioning

confidence: 99%

Section: Mechanisms Of Gpcr Ciliary Localization 671mentioning

confidence: 99%

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

Brear

Yoon

Wojtyniak³

et al. 2014

Genetics

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“…Mechanistic details of transport of membrane-associated proteins are unknown. A vesicular transport pathway for rhodopsin from the endoplasmic reticulum to the outer segments has been firmly established (47)(48)(49)(50). Transmembrane GCs probably follow a similar pathway.…”

Section: Figure 8 Ultrastructure Of Wt (A and B) And Degenerative Gc1mentioning

confidence: 96%

The Function of Guanylate Cyclase 1 and Guanylate Cyclase 2 in Rod and Cone Photoreceptors

Baehr

Karan

Maeda

et al. 2007

Journal of Biological Chemistry

148

246

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Retinal guanylate cyclases 1 and 2 (GC1 and GC2) are responsible for synthesis of cyclic GMP in rods and cones, but their individual contributions to phototransduction are unknown. We report here that the deletion of both GC1 and GC2 rendered rod and cone photoreceptors nonfunctional and unstable. In the rod outer segments of GC double knock-out mice, guanylate cyclase-activating proteins 1 and 2, and cyclic GMP phosphodiesterase were undetectable, although rhodopsin and transducin ␣-subunit were mostly unaffected. Outer segment membranes of GC1 ؊/؊ and GC double knock-out cones were destabilized and devoid of cone transducin (␣-and ␥-subunits), cone phosphodiesterase, and G protein-coupled receptor kinase 1, whereas cone pigments were present at reduced levels. Real time reverse transcription-PCR analyses demonstrated normal RNA transcript levels for the downregulated proteins, indicating that down-regulation is posttranslational. We interpret these results to demonstrate an intrinsic requirement of GCs for stability and/or transport of a set of membrane-associated phototransduction proteins.

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“…Arf4 regulates trafficking to the cilium through interaction with cargo at the TGN ) (see main poster panel). Arf4 specifically recognizes the VxPx cytosolic targeting motif in retinal rhodopsin to facilitate its transport into the rod outer segment, a specialized cilium (Deretic et al, 2005). This ciliary targeting complex includes Rab11, FIP3 (a dual Arf and Rab11 effector) and ASAP1, an Arf GAP .…”

Section: Arf Proteins and Their Regulatorsmentioning

confidence: 99%

Arfs at a Glance

Jackson

Bouvet

2014

Journal of Cell Science

119

117

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The Arf small G proteins regulate protein and lipid trafficking in eukaryotic cells through a regulated cycle of GTP binding and hydrolysis. In their GTP-bound form, Arf proteins recruit a specific set of protein effectors to the membrane surface. These effectors function in vesicle formation and tethering, non-vesicular lipid transport and cytoskeletal regulation. Beyond fundamental membrane trafficking roles, Arf proteins also regulate mitosis, plasma membrane signaling, cilary trafficking and lipid droplet function. Tight spatial and temporal regulation of the relatively small number of Arf proteins is achieved by their guanine nucleotideexchange factors (GEFs) and GTPase-activating proteins (GAPs), which catalyze GTP binding and hydrolysis, respectively. A unifying function of Arf proteins, performed in conjunction with their regulators and effectors, is sensing, modulating and transporting the lipids that make up cellular membranes. In this Cell Science at a Glance article and the accompanying poster, we discuss the unique features of Arf small G proteins, their functions in vesicular and lipid trafficking in cells, and how these functions are modulated by their regulators, the GEFs and GAPs. We also discuss how these Arf functions are subverted by human pathogens and disease states.

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Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADP-ribosylation factor 4 (ARF4)

Cited by 183 publications

References 41 publications

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

The Function of Guanylate Cyclase 1 and Guanylate Cyclase 2 in Rod and Cone Photoreceptors

Arfs at a Glance

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