@article{HankeGogokhiaFrederickZhangetal.2018,
  author    = {Hanke-Gogokhia, Christin and Frederick, Jeanne M. and Zhang, Houbin and Baehr, Wolfgang},
  title     = {Binary Function of ARL3-GTP Revealed by Gene Knockouts},
  series = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy},
  volume    = {1074},
  journal   = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy},
  publisher = {Springer},
  address   = {Cham},
  isbn      = {978-3-319-75402-4},
  issn      = {0065-2598},
  doi       = {10.1007/978-3-319-75402-4_39},
  pages     = {317 -- 325},
  year      = {2018},
  abstract  = {UNC119 and PDE delta are lipid-binding proteins and are thought to form diffusible complexes with transducin-alpha 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.},
  language  = {en}
}
@inproceedings{HankeGogokhiaFrederickZhangetal.2015,
  author    = {Hanke-Gogokhia, Christin and Frederick, Jeanne M. and Zhang, Houbin and Baehr, Wolfgang},
  title     = {ARL3 regulates transport of prenylated and acylated proteins to photoreceptor outer segment in mouse retina},
  series = {Investigative ophthalmology \& visual science},
  volume    = {56},
  booktitle = {Investigative ophthalmology \& visual science},
  number    = {7},
  publisher = {Association for Research in Vision and Opthalmology},
  address   = {Rockville},
  issn      = {0146-0404},
  pages     = {2},
  year      = {2015},
  language  = {en}
}
@article{HankeGogokhiaWuGerstneretal.2016,
  author    = {Hanke-Gogokhia, Christin and Wu, Zhijian and Gerstner, Cecilia D. and Frederick, Jeanne M. and Zhang, Houbin and Baehr, Wolfgang},
  title     = {Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors},
  series = {The journal of biological chemistry},
  volume    = {291},
  journal   = {The journal of biological chemistry},
  publisher = {American Society for Biochemistry and Molecular Biology},
  address   = {Bethesda},
  issn      = {0021-9258},
  doi       = {10.1074/jbc.M115.710954},
  pages     = {7142 -- 7155},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@article{HankeGogokhiaZhangFredericketal.2016,
  author    = {Hanke-Gogokhia, Christin and Zhang, Houbin and Frederick, Jeanne M. and Baehr, Wolfgang},
  title     = {The Function of Arf-like Proteins ARL2 and ARL3 in Photoreceptors},
  series = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy},
  volume    = {854},
  journal   = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy},
  editor    = {Rickman, CB and LaVail, MM and Anderson, RE and Grimm, C and Hollyfield, J and Ash, J},
  publisher = {Springer International Publishing AG},
  address   = {Cham},
  isbn      = {978-3-319-17121-0; 978-3-319-17120-3},
  issn      = {0065-2598},
  doi       = {10.1007/978-3-319-17121-0_87},
  pages     = {655 -- 661},
  year      = {2016},
  abstract  = {Arf-like proteins (ARLs) are ubiquitously expressed small G proteins of the RAS superfamily. In photoreceptors, ARL2 and ARL3 participate in the trafficking of lipidated membrane-associated proteins and colocalize in the inner segment with UNC119A and PDE delta. UNC119A and PDE delta are acyl-and prenyl-binding proteins, respectively, involved in trafficking of acylated (transducin-alpha subunit, nephrocystin NPHP3) and prenylated proteins (GRK1, PDE6). Germline Arl3 knockout mice do not survive beyond postnatal day 21 and display ciliary defects in multiple organs (kidney, liver and pancreas) as well as retinal degeneration. Conditional knockouts will be necessary to delineate mechanisms of protein transport in retina disease.},
  language  = {en}
}
@article{AndresHankeBaxaetal.2010,
  author    = {Andres, Dorothee and Hanke, Christin and Baxa, Ulrich and Seul, Anait and Barbirz, Stefanie and Seckler, Robert},
  title     = {Tailspike interactions with lipopolysaccharide effect DNA ejection from phage P22 particles in vitro},
  issn      = {0021-9258},
  doi       = {10.1074/jbc.M110.169003},
  year      = {2010},
  abstract  = {Initial attachment of bacteriophage P22 to the Salmonella host cell is known to be mediated by interactions between lipopolysaccharide (LPS) and the phage tailspike proteins (TSP), but the events that subsequently lead to DNA injection into the bacterium are unknown. We used the binding of a fluorescent dye and DNA accessibility to DNase and restriction enzymes to analyze DNA ejection from phage particles in vitro. Ejection was specifically triggered by aggregates of purified Salmonella LPS but not by LPS with different O-antigen structure, by lipid A, phospholipids, or soluble O-antigen polysaccharide. This suggests that P22 does not use a secondary receptor at the bacterial outer membrane surface. Using phage particles reconstituted with purified mutant TSP in vitro, we found that the endorhamnosidase activity of TSP degrading the O-antigen polysaccharide was required prior to DNA ejection in vitro and DNA replication in vivo. If, however, LPS was pre-digested with soluble TSP, it was no longer able to trigger DNA ejection, even though it still contained five O-antigen oligosaccharide repeats. Together with known data on the structure of LPS and phage P22, our results suggest a molecular model. In this model, tail-spikes position the phage particles on the outer membrane surface for DNA ejection. They force gp26, the central needle and plug protein of the phage tail machine, through the core oligosaccharide layer and into the hydrophobic portion of the outer membrane, leading to refolding of the gp26 lazo-domain, release of the plug, and ejection of DNA and pilot proteins.},
  language  = {en}
}
@phdthesis{HankeGogokhia2016,
  author    = {Hanke-Gogokhia, Christin},
  title     = {Small GTPase ARL3-GTP is key molecule in transition zone formation and trafficking of ciliary cargo in mouse photoreceptors},
  school      = {Universit{\"a}t Potsdam},
  pages     = {166},
  year      = {2016},
  language  = {en}
}
@article{AndresBaxaHankeetal.2010,
  author    = {Andres, Dorothee and Baxa, Ulrich and Hanke, Christin and Seckler, Robert and Barbirz, Stefanie},
  title     = {Carbohydrate binding of Salmonella phage P22 tailspike protein and its role during host cell infection},
  issn      = {0300-5127},
  doi       = {10.1042/Bst0381386},
  year      = {2010},
  abstract  = {TSPs (tailspike proteins) are essential infection organelles of bacteriophage P22. Upon infection, P22TSP binds to and cleaves the O-antigen moiety of the LPS (lipopolysaccharide) of its Salmonella host To elucidate the role of TSP during infection, we have studied binding to oligosaccharides and polysaccharides of Salmonella enteric Typhimurium and Enteritidis in vitro. P22TSP is a trimeric beta-helical protein with a carbohydrate-binding site on each subunit. Octasaccharide O-antigen fragments bind to P22TSP with micromolar dissociation constants. Moreover, P22TSP is an endorhamnosidase and cleaves the host O-antigen. Catalytic residues lie at the periphery of the high-affinity binding site, which enables unproductive binding modes, resulting in slow hydrolysis. However, the role of this hydrolysis function during infection remains unclear. Binding of polysaccharide to P22TSP is of high avidity with slow dissociation rates when compared with oligosaccharides. In vivo, the infection of Salmonella with phage P22 can be completely inhibited by the addition of LPS, indicating that binding of phage to its host via TSP is an essential step for infection.},
  language  = {en}
}
@article{ZhangHankeGogokhiaJiangetal.2015,
  author    = {Zhang, Houbin and Hanke-Gogokhia, Christin and Jiang, Li and Li, Xiaobo and Wang, Pu and Gerstner, Cecilia D. and Frederick, Jeanne M. and Yang, Zhenglin and Baehr, Wolfgang},
  title     = {Mistrafficking of prenylated proteins causes retinitis pigmentosa 2},
  series = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  volume    = {29},
  journal   = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  number    = {3},
  publisher = {Federation of American Societies for Experimental Biology},
  address   = {Bethesda},
  issn      = {0892-6638},
  doi       = {10.1096/fj.14-257915},
  pages     = {932 -- 942},
  year      = {2015},
  abstract  = {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.},
  language  = {en}
}
@article{RonquilloHankeGogokhiaReveloetal.2016,
  author    = {Ronquillo, Cecinio C. and Hanke-Gogokhia, Christin and Revelo, Monica P. and Frederick, Jeanne M. and Jiang, Li and Baehr, Wolfgang},
  title     = {Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation},
  series = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  volume    = {30},
  journal   = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  publisher = {Federation of American Societies for Experimental Biology},
  address   = {Bethesda},
  issn      = {0892-6638},
  doi       = {10.1096/fj.201600511R},
  pages     = {3400 -- 3412},
  year      = {2016},
  abstract  = {Null mutations in the human IQCB1/NPHP5 (nephrocystin-5) gene that encodes NPHP5 are the most frequent cause of Senior-LOken syndrome, a ciliopathy that is characterized by Leber congenital amaurosis and nephronophthisis. We generated germline Nphp5-knockout mice by placing a -Geo gene trap in intron 4, thereby truncating NPHP5 at Leu87 and removing all known functional domains. At eye opening, Nphp5(-/-) mice exhibited absence of scotopic and photopic electroretinogram responses, a phenotype that resembles Leber congenital amaurosis. Outer segment transmembrane protein accumulation in Nphp5(-/-) endoplasmic reticulum was evident as early as postnatal day (P)6. EGFP-CETN2, a centrosome and transition zone marker, identified basal bodies in Nphp5(-/-) photoreceptors, but without fully developed transition zones. Ultrastructure of P6 and 10 Nphp5(-/-) photoreceptors revealed aberrant transition zones of reduced diameter. Nphp5(-/-) photoreceptor degeneration was complete at 1 mo of age but was delayed significantly in Nphp5(-/-);Nrl(-/-) (cone only) retina. Nphp5(-/-) mouse embryonic fibroblast developed normal cilia, and Nphp5(-/-) kidney histology at 1 yr of age showed no significant pathology. Results establish that nephrocystin-5 is essential for photoreceptor outer segment formation but is dispensable for kidney and mouse embryonic fibroblast ciliary formation.},
  language  = {en}
}