Abstract
UNC119 and PDEδ are lipid-binding proteins and are thought to form diffusible complexes with transducin-α and prenylated OS proteins, respectively, to mediate their trafficking to photoreceptor outer segments. Here, we investigate mechanisms of trafficking which are controlled by Arf-like protein 3 (Arl3), a small GTPase. The activity of ARL3 is regulated by a GEF (ARL13b) and a GAP (RP2). In a mouse germline knockout of RP2, ARL3-GTP is abundant as its intrinsic GTPase activity is extremely low. High levels of ARL3-GTP impair binding and trafficking of cargo to the outer segment. Germline knockout of ARL3 is embryonically lethal generating a syndromic ciliopathy-like phenotype. Retina- and rod-specific knockout of ARL3 allow to determine the precise mechanisms leading to photoreceptor degeneration. The knockouts reveal binary functions of ARL3-GTP as a key molecule in late-stage photoreceptor ciliogenesis and cargo displacement factor.
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References
Arshavsky VY, Lamb TD, Pugh EN Jr (2002) G proteins and phototransduction. Annu Rev Physiol 64:153–187
Baehr W, Devlin MJ, Applebury ML (1979) Isolation and characterization of cGMP phosphodiesterase from bovine rod outer segments. J Biol Chem 254:11669–11677
Cantagrel V, Silhavy JL, Bielas SL et al (2008) Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet 83:170–179
Caspary T, Larkins CE, Anderson KV (2007) The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell 12:767–778
Constantine R, Zhang H, Gerstner CD et al (2012) Uncoordinated (UNC)119: coordinating the trafficking of myristoylated proteins. Vis Res 75:26–32
Duldulao NA, Lee S, Sun Z (2009) Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development 136:4033–4042
Fung BKK, Young JH, Yamane HK et al (1990) Subunit stoichiometry of retinal rod cGMP phosphodiesterase. Biochemistry 29:2657–2664
Gilliam JC, Chang JT, Sandoval IM et al (2012) Three-dimensional architecture of the rod sensory cilium and its disruption in retinal neurodegeneration. Cell 151:1029–1041
Gotthardt K, Lokaj M, Koerner C et al (2015) A G-protein activation cascade from Arl13b to Arl3 and implications for ciliary targeting of lipidated proteins. elife 4:e11859
Hanke-Gogokhia C, Wu Z, Gerstner CD et al (2016) Arf-like protein 3 (ARL3) regulates protein trafficking and ciliogenesis in mouse photoreceptors. J Biol Chem 291:7142–7155
Hanzal-Bayer M, Renault L, Roversi P et al (2002) The complex of Arl2-GTP and PDE delta: from structure to function. EMBO J 21:2095–2106
Jayasundera T, Branham KE, Othman M et al (2010) RP2 phenotype and pathogenetic correlations in X-linked retinitis pigmentosa. Arch Ophthalmol 128:915–923
Kobayashi A, Higashide T, Hamasaki D et al (2000) HRG4 (UNC119) mutation found in cone-rod dystrophy causes retinal degeneration in a transgenic model. Invest Ophthalmol Vis Sci 41:3268–3277
Kuhnel K, Veltel S, Schlichting I et al (2006) Crystal structure of the human retinitis pigmentosa 2 protein and its interaction with Arl3. Structure 14:367–378
Maeda T, Imanishi Y, Palczewski K (2003) Rhodopsin phosphorylation: 30 years later. Prog Retin Eye Res 22:417–434
Manolaridis I, Kulkarni K, Dodd RB et al (2013) Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1. Nature 504:301–305
Palczewski K, Benovic JL (1991) G-protein-coupled receptor kinases. TIBS 16:387–391
Schrick JJ, Vogel P, Abuin A et al (2006) ADP-ribosylation factor-like 3 is involved in kidney and photoreceptor development. Am J Pathol 168:1288–1298
Strom SP, Clark MJ, Martinez A et al (2016) De novo occurrence of a variant in ARL3 and apparent autosomal dominant transmission of retinitis pigmentosa. PLoS One 11:e0150944
Thomas S, Wright KJ, Le CS et al (2014) A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum Mutat 35:137–146
Veltel S, Gasper R, Eisenacher E et al (2008) The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3. Nat Struct Mol Biol 15:373–380
Wright AF, Chakarova CF, Abd El-Aziz MM et al (2010) Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11:273–284
Young RW (1976) Visual cells and the concept of renewal. Invest Ophthalmol Vis Sci 15:700–725
Zhang H, Li S, Doan T et al (2007) Deletion of PrBP/{delta} impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments. Proc Natl Acad Sci U S A 104:8857–8862
Zhang H, Constantine R, Vorobiev S et al (2011) UNC119 is required for G protein trafficking in sensory neurons. Nat Neurosci 14:874–880
Zhang H, Constantine R, Frederick JM et al (2012) The prenyl-binding protein PrBP/delta: a chaperone participating in intracellular trafficking. Vis Res 75:19–25
Zhang H, Hanke-Gogokhia C, Jiang L et al (2015) Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. FASEB J 29:932–942
Acknowledgments
This research was supported by a National Eye Institute grants EY08123, EY019298 (WB), EY014800-039003 (NEI core grant), unrestricted grants to the Departments of Ophthalmology at the University of Utah from Research to Prevent Blindness (RPB; New York), the Retina Research Foundation, Houston (Alice McPherson, MD), and the Foundation for Retina Research (David Brint, MD). WB is a recipient of a Research to Prevent Blindness Senior Investigator and Nelson Trust Award.
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Hanke-Gogokhia, C., Frederick, J.M., Zhang, H., Baehr, W. (2018). Binary Function of ARL3-GTP Revealed by Gene Knockouts. In: Ash, J., Anderson, R., LaVail, M., Bowes Rickman, C., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1074. Springer, Cham. https://doi.org/10.1007/978-3-319-75402-4_39
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DOI: https://doi.org/10.1007/978-3-319-75402-4_39
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