TY  - JOUR
A1  - Hanke-Gogokhia, Christin
A1  - Wu, Zhijian
A1  - Gerstner, Cecilia D.
A1  - Frederick, Jeanne M.
A1  - Zhang, Houbin
A1  - Baehr, Wolfgang
T1  - Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors
JF  - The journal of biological chemistry
N2  - Arf-like protein 3 (ARL3) is a ubiquitous small GTPase expressed in ciliated cells of plants and animals. Germline deletion of Arl3 in mice causes multiorgan ciliopathy reminiscent of Bardet-Biedl or Joubert syndromes. As photoreceptors are elegantly compartmentalized and have cilia, we probed the function of ARL3 (ADP-ribosylation factor (Arf)-like 3 protein) by generating rod photoreceptor-specific (prefix (rod)) and retina-specific (prefix (ret)) Arl3 deletions. In predegenerate (rod)Arl3(-/-) mice, lipidated phototransduction proteins showed trafficking deficiencies, consistent with the role of ARL3 as a cargo displacement factor for lipid-binding proteins. By contrast, (ret)Arl3(-/-) rods and cones expressing Cre recombinase during embryonic development formed neither connecting cilia nor outer segments and degenerated rapidly. Absence of cilia infers participation of ARL3 in ciliogenesis and axoneme formation. Ciliogenesis was rescued, and degeneration was reversed in part by subretinal injection of adeno-associated virus particles expressing ARL3-EGFP. The conditional knock-out phenotypes permitted identification of two ARL3 functions, both in the GTP-bound form as follows: one as a regulator of intraflagellar transport participating in photoreceptor ciliogenesis and the other as a cargo displacement factor transporting lipidated protein to the outer segment. Surprisingly, a farnesylated inositol polyphosphate phosphatase only trafficked from the endoplasmic reticulum to the Golgi, thereby excluding it from a role in photoreceptor cilia physiology.
KW  - animal model
KW  - gene knock-out
KW  - lipid-binding protein
KW  - photoreceptor
KW  - protein trafficking (Golgi)
KW  - retinal degeneration
Y1  - 2016
U6  - https://doi.org/10.1074/jbc.M115.710954
SN  - 0021-9258
SN  - 1083-351X
VL  - 291
SP  - 7142
EP  - 7155
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Zhang, Houbin
A1  - Hanke-Gogokhia, Christin
A1  - Jiang, Li
A1  - Li, Xiaobo
A1  - Wang, Pu
A1  - Gerstner, Cecilia D.
A1  - Frederick, Jeanne M.
A1  - Yang, Zhenglin
A1  - Baehr, Wolfgang
T1  - Mistrafficking of prenylated proteins causes retinitis pigmentosa 2
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - 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 6 Delta (PDE6D), a prenyl-binding 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.
KW  - rod-cone dystrophy
KW  - ARL3
KW  - PDE6D
KW  - RP2
KW  - XLRP
Y1  - 2015
U6  - https://doi.org/10.1096/fj.14-257915
SN  - 0892-6638
SN  - 1530-6860
VL  - 29
IS  - 3
SP  - 932
EP  - 942
PB  - Federation of American Societies for Experimental Biology
CY  - Bethesda
ER  -