Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors
- 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 virusArf-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.…
Author details: | Christin Hanke-Gogokhia, Zhijian Wu, Cecilia D. Gerstner, Jeanne M. Frederick, Houbin ZhangORCiD, Wolfgang BaehrORCiD |
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DOI: | https://doi.org/10.1074/jbc.M115.710954 |
ISSN: | 0021-9258 |
ISSN: | 1083-351X |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/26814127 |
Title of parent work (English): | The journal of biological chemistry |
Publisher: | American Society for Biochemistry and Molecular Biology |
Place of publishing: | Bethesda |
Publication type: | Article |
Language: | English |
Year of first publication: | 2016 |
Publication year: | 2016 |
Release date: | 2020/03/22 |
Tag: | animal model; gene knock-out; lipid-binding protein; photoreceptor; protein trafficking (Golgi); retinal degeneration |
Volume: | 291 |
Number of pages: | 14 |
First page: | 7142 |
Last Page: | 7155 |
Funding institution: | National Institutes of Health [EY08123, EY019298]; NEI Core [EY014800-039003]; Research to Prevent Blindness (New York); National Science Foundation of China [81371030]; Science and Technology Department of Sichuan [2014HH0009] |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
Peer review: | Referiert |