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Nachiket Devdatta Pendse, Martin Bergo, Stephen Young, Visvanathan Ramamurthy; Geranylgeranylation of retinal proteins is essential for cone photoreceptor function and survival. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1322.
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© ARVO (1962-2015); The Authors (2016-present)
Protein prenylation is the post-translational addition of a lipid, either a 15-carbon farnesyl group catalyzed by protein farnesyltransferase (FTase) or a 20-carbon geranylgeranyl group catalyzed by protein geranylgeranytransferase (GGTase). Despite the prevalence of this posttranslational modification, the in vivo importance of this modification in photoreceptors is not clear. Protein prenylation is thought to be needed for membrane anchorage, protein-protein interactions, and trafficking and retention of proteins in outer segment (OS) of photoreceptors. Our goal is to decipher the importance of this common protein modification in cone photoreceptor cells.
In this study, we eliminated Fntb, the catalytic subunit of FTase, or Pggt1b, the catalytic subunit of GGTase, in cone photoreceptors with Cre-loxP recombination. To assess the function of cone photoreceptor cells, we performed electroretinograms (ERGs). Using immunocytochemistry, we investigated retinal morphology and the localization of outer segment proteins. Western blots were used to determine levels of OS proteins. All experiments utilized littermate controls (n = 4).
Retinal development progressed normally in mice lacking protein geranylgeranylation or protein farnesylation. However, in the absence of Pggt1b, cone function was reduced at postnatal day 16 (P16) which was completely lost at P25. In contrast, loss of Fntb in cones did not affect cone function up to 4 months. Loss of photopic response in Pggt1b-null mice correlated with a major reduction (82%, p<0.01; n=4) in the level of cone phosphodiesterases6 (PDE6) at P25. Remarkably, trafficking of residual cone PDE6 to the cone OS was unaffected by a deficiency of Pggt1b.
Our results demonstrate that the protein geranylgeranylation is crucial for normal cone photoreceptor function. This cone dysfunction is likely due to decreased stability of cone PDE6 in the absence of the geranylgeranyl lipid anchor. Surprisingly, lack of geranylgeranylation did not affect trafficking of cone PDE6 to the cone OS.
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