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Mistrafficking of prenylated proteins causes retinitis pigmentosa 2
Author(s) -
Zhang Houbin,
HankeGogokhia Christin,
Jiang Li,
Li Xiaobo,
Wang Pu,
Gerstner Cecilia D.,
Frederick Jeanne M.,
Yang Zhenglin,
Baehr Wolfgang
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-257915
Subject(s) - retinitis pigmentosa , prenylation , gtpase , biology , gtp' , dystrophy , protein subunit , rhodopsin , heterotrimeric g protein , microbiology and biotechnology , genetics , g protein , gene , biochemistry , retinal , signal transduction , enzyme
The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase‐activating protein (GAP) for ARL3 (Arf‐like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase ± Δ (PDE6D), a prenylbinding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X‐linked retinitis pigmentosa (XLRP) and cone‐rod dystrophy (XL‐CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The Rp2h –/– mice exhibited a slowly progressing rod‐cone dystrophy simulating the human disease. Rp2h –/– scotopic a‐wave and photopic b‐wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G‐protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the Rp2h –/– outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3‐GTP levels, forcing PDE6D to assume a predominantly “closed” conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3‐GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod‐cone dystrophy.—Zhang, H., Hanke‐Gogokhia, C., Jiang, L., Li, X., Wang, P., Gerstner, C. D., Frederick, J. M., Yang, Z., Baehr, W., Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. FASEB J. 29, 932–942 (2015). www.fasebj.org