Murphy Joseph, Kolandaivelu Saravanan
From the Department of Ophthalmology, West Virginia University Eye institute, Morgantown, West Virginia 26506.
From the Department of Ophthalmology, West Virginia University Eye institute, Morgantown, West Virginia 26506
J Biol Chem. 2016 Oct 28;291(44):23036-23046. doi: 10.1074/jbc.M116.742767. Epub 2016 Sep 9.
Progressive rod-cone degeneration (PRCD) is a photoreceptor outer segment (OS) disc-specific protein with unknown function that is associated with retinitis pigmentosa (RP). The most common mutation in PRCD linked with severe RP phenotype is substitution of the only cysteine to tyrosine (C2Y). In this study, we find that PRCD is post-translationally modified by a palmitoyl lipid group at the cysteine residue linked with RP. Disrupting PRCD palmitoylation either chemically or by genetically eliminating the modified cysteine dramatically affects the stability of PRCD. Furthermore, in vivo electroporation of PRCD C2Y mutant in the mouse retina demonstrates that the palmitoylation of PRCD is important for its proper localization in the photoreceptor OS. Mutant PRCD C2Y was found in the inner segment in contrast to normal localization of WT PRCD in the OS. Our results also suggest that zDHHC3, a palmitoyl acyltransferase (PAT), catalyzes the palmitoylation of PRCD in the Golgi compartment. In conclusion, we find that the palmitoylation of PRCD is crucial for its trafficking to the photoreceptor OS and mislocalization of this protein likely leads to RP-related phenotypes.
进行性视杆-视锥变性（PRCD）是一种功能未知的光感受器外段（OS）盘特异性蛋白，与色素性视网膜炎（RP）相关。与严重RP表型相关的PRCD中最常见的突变是唯一的半胱氨酸被酪氨酸取代（C2Y）。在本研究中，我们发现PRCD在与RP相关的半胱氨酸残基处被棕榈酰脂质基团进行翻译后修饰。通过化学方法或通过基因敲除修饰的半胱氨酸来破坏PRCD棕榈酰化，会显著影响PRCD的稳定性。此外，在小鼠视网膜中对PRCD C2Y突变体进行体内电穿孔表明，PRCD的棕榈酰化对其在光感受器OS中的正确定位很重要。与野生型PRCD在OS中的正常定位相反，突变型PRCD C2Y在内段中被发现。我们的结果还表明，棕榈酰酰基转移酶（PAT）zDHHC3在高尔基体中催化PRCD的棕榈酰化。总之，我们发现PRCD的棕榈酰化对其运输到光感受器OS至关重要，并且该蛋白的错误定位可能导致与RP相关的表型。
