Binary Function of ARL3-GTP Revealed by Gene Knockouts

Christin Hanke-Gogokhia; Jeanne M Frederick; Houbin Zhang; Wolfgang Baehr

doi:10.1007/978-3-319-75402-4_39

Binary Function of ARL3-GTP Revealed by Gene Knockouts

Adv Exp Med Biol. 2018:1074:317-325. doi: 10.1007/978-3-319-75402-4_39.

Authors

Christin Hanke-Gogokhia^{1

2}, Jeanne M Frederick³, Houbin Zhang^{4

5}, Wolfgang Baehr^{6

7

8}

Affiliations

¹ Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA. [email protected].
² Department of Biochemistry and Biology, University of Potsdam, Potsdam, Germany. [email protected].
³ Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁴ The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
⁵ School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
⁶ Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA. [email protected].
⁷ Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT, USA. [email protected].
⁸ Department of Biology, University of Utah, Salt Lake City, UT, USA. [email protected].

PMID: 29721959
DOI: 10.1007/978-3-319-75402-4_39

Abstract

UNC119 and PDEδ are lipid-binding proteins and are thought to form diffusible complexes with transducin-α 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.

Keywords: ARL13b; ARL3; Germline knockout; PDEδ; Photoreceptor; RP2; Retina disease; UNC119.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

ADP-Ribosylation Factors / deficiency
ADP-Ribosylation Factors / genetics
ADP-Ribosylation Factors / physiology*
Adaptor Proteins, Signal Transducing / metabolism
Animals
Ciliopathies / genetics
Ciliopathies / metabolism
Ciliopathies / pathology
Cone-Rod Dystrophies / genetics
Cone-Rod Dystrophies / metabolism
Cone-Rod Dystrophies / pathology
Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism
GTP-Binding Proteins
Genes, Lethal
Guanosine Triphosphate / metabolism
Lipoproteins / metabolism
Membrane Proteins / metabolism
Mice
Mice, Knockout
Organ Specificity
Protein Prenylation
Protein Transport / physiology*
Pyrophosphatases / deficiency
Pyrophosphatases / physiology
Rod Cell Outer Segment / metabolism

Substances

Adaptor Proteins, Signal Transducing
Arl13b protein, mouse
Lipoproteins
Membrane Proteins
RP2 protein, mouse
Unc119 protein, mouse
Guanosine Triphosphate
Cyclic Nucleotide Phosphodiesterases, Type 6
GTP-Binding Proteins
Pyrophosphatases
Arl3 protein, mouse
ADP-Ribosylation Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding