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???displayArticle.abstract??? Rhodopsin mislocalization is frequently observed in retinitis pigmentosa (RP) patients. For example, class I mutant rhodopsin is deficient in the VxPx trafficking signal, mislocalizes to the plasma membrane (PM) of rod photoreceptor inner segments (ISs), and causes autosomal dominant RP. Mislocalized rhodopsin causes photoreceptor degeneration in a manner independent of light-activation. In this manuscript, we took advantage of Xenopus laevis models of both sexes expressing wild-type human rhodopsin or its class I Q344ter mutant fused to Dendra2 fluorescent protein to characterize a novel light-independent mechanism of photoreceptor degeneration caused by mislocalized rhodopsin. We found that rhodopsin mislocalized to the PM is actively internalized and transported to lysosomes where it is degraded. This degradation process results in the downregulation of a crucial component of the photoreceptor IS PM: the sodium-potassium ATPase α-subunit (NKAα). The downregulation of NKAα is not because of decreased NKAα mRNA, but due to cotransport of mislocalized rhodopsin and NKAα to lysosomes or autophagolysosomes. In a separate set of experiments, we found that class I mutant rhodopsin, which causes NKAα downregulation, also causes shortening and loss of rod outer segments (OSs); the symptoms frequently observed in the early stages of human RP. Likewise, pharmacological inhibition of NKAα led to shortening and loss of rod OSs. These combined studies suggest that mislocalized rhodopsin leads to photoreceptor dysfunction through disruption of the PM protein homeostasis and compromised NKAα function. This study unveiled a novel role of lysosome-mediated degradation in causing inherited disorders manifested by mislocalization of ciliary receptors.SIGNIFICANCE STATEMENT Retinal ciliopathy is the most common form of inherited blinding disorder frequently manifesting rhodopsin mislocalization. Our understanding of the relationships between rhodopsin mislocalization and photoreceptor dysfunction/degeneration has been far from complete. This study uncovers a hitherto uncharacterized consequence of rhodopsin mislocalization: the activation of the lysosomal pathway, which negatively regulates the amount of the sodium-potassium ATPase (NKAα) on the inner segment plasma membrane. On the plasma membrane, mislocalized rhodopsin extracts NKAα and sends it to lysosomes where they are co-degraded. Compromised NKAα function leads to shortening and loss of the photoreceptor outer segments as observed for various inherited blinding disorders. In summary, this study revealed a novel pathogenic mechanism applicable to various forms of blinding disorders caused by rhodopsin mislocalization.
Adamian,
Rod and cone opsin mislocalization in an autopsy eye from a carrier of X-linked retinitis pigmentosa with a Gly436Asp mutation in the RPGR gene.
2006, Pubmed
Adamian,
Rod and cone opsin mislocalization in an autopsy eye from a carrier of X-linked retinitis pigmentosa with a Gly436Asp mutation in the RPGR gene.
2006,
Pubmed Adams,
The retinal ciliopathies.
2007,
Pubmed Alfinito,
Activation of mislocalized opsin kills rod cells: a novel mechanism for rod cell death in retinal disease.
2002,
Pubmed Arikawa,
Localization of peripherin/rds in the disk membranes of cone and rod photoreceptors: relationship to disk membrane morphogenesis and retinal degeneration.
1992,
Pubmed Besharse,
Turnover of rod photoreceptor outer segments. II. Membrane addition and loss in relationship to light.
1977,
Pubmed
,
Xenbase Bogéa,
Light Induces Ultrastructural Changes in Rod Outer and Inner Segments, Including Autophagy, in a Transgenic Xenopus laevis P23H Rhodopsin Model of Retinitis Pigmentosa.
2015,
Pubmed
,
Xenbase Chen,
Autophagy protects the retina from light-induced degeneration.
2013,
Pubmed Choi,
Cone degeneration following rod ablation in a reversible model of retinal degeneration.
2011,
Pubmed
,
Xenbase Chu,
The appearance of acetylated alpha-tubulin during early development and cellular differentiation in Xenopus.
1989,
Pubmed
,
Xenbase Concepcion,
Q344ter mutation causes mislocalization of rhodopsin molecules that are catalytically active: a mouse model of Q344ter-induced retinal degeneration.
2010,
Pubmed Demontis,
Effect of blocking the Na+/K+ ATPase on Ca2+ extrusion and light adaptation in mammalian retinal rods.
1995,
Pubmed De Munari,
Structure-based design and synthesis of novel potent Na+,K+ -ATPase inhibitors derived from a 5alpha,14alpha-androstane scaffold as positive inotropic compounds.
2003,
Pubmed Deretic,
Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADP-ribosylation factor 4 (ARF4).
2005,
Pubmed Edward,
An immunohistochemical study of opsin in photoreceptor cells following light-induced retinal degeneration in the rat.
1993,
Pubmed Fariss,
Evidence from normal and degenerating photoreceptors that two outer segment integral membrane proteins have separate transport pathways.
1997,
Pubmed Fliegauf,
When cilia go bad: cilia defects and ciliopathies.
2007,
Pubmed Friedrich,
The Na/K-ATPase is obligatory for membrane anchorage of retinoschisin, the protein involved in the pathogenesis of X-linked juvenile retinoschisis.
2011,
Pubmed Gable,
Comparison of Digitalis Sensitivities of Na+/K+-ATPases from Human and Pig Kidneys.
2017,
Pubmed Gao,
Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) gene.
2002,
Pubmed Hagstrom,
A role for the Tubby-like protein 1 in rhodopsin transport.
2001,
Pubmed Koch,
Halting progressive neurodegeneration in advanced retinitis pigmentosa.
2015,
Pubmed Laird,
Identification of a VxP Targeting Signal in the Flagellar Na+ /K+ -ATPase.
2015,
Pubmed
,
Xenbase Landfried,
Digoxin-induced retinal degeneration depends on rhodopsin.
2017,
Pubmed Lebovitz,
Molecular characterization and expression of the (Na+ + K+)-ATPase alpha-subunit in Drosophila melanogaster.
1989,
Pubmed Lessieur,
The Ciliopathy Gene ahi1 Is Required for Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival.
2017,
Pubmed Li,
Rod photoreceptor neurite sprouting in retinitis pigmentosa.
1995,
Pubmed Lodowski,
Signals governing the trafficking and mistrafficking of a ciliary GPCR, rhodopsin.
2013,
Pubmed
,
Xenbase Lodowski,
Monitoring of rhodopsin trafficking and mistrafficking in live photoreceptors.
2015,
Pubmed
,
Xenbase Luan,
Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration.
2014,
Pubmed Mahanty,
Suitable reference gene for quantitative real-time PCR analysis of gene expression in gonadal tissues of minnow Puntius sophore under high-temperature stress.
2017,
Pubmed Mani,
Xenopus rhodopsin promoter. Identification of immediate upstream sequences necessary for high level, rod-specific transcription.
2001,
Pubmed
,
Xenbase Milam,
Histopathology of the human retina in retinitis pigmentosa.
1998,
Pubmed Milam,
Clinicopathologic effects of the Q64ter rhodopsin mutation in retinitis pigmentosa.
1996,
Pubmed Molday,
Retinoschisin (RS1), the protein encoded by the X-linked retinoschisis gene, is anchored to the surface of retinal photoreceptor and bipolar cells through its interactions with a Na/K ATPase-SARM1 complex.
2007,
Pubmed Molthagen,
Apoptotic cell death of photoreceptor cells in mice deficient for the adhesion molecule on glia (AMOG, the beta 2- subunit of the Na, K-ATPase).
1996,
Pubmed Moritz,
A functional rhodopsin-green fluorescent protein fusion protein localizes correctly in transgenic Xenopus laevis retinal rods and is expressed in a time-dependent pattern.
2001,
Pubmed
,
Xenbase Nathans,
Rhodopsin: structure, function, and genetics.
1992,
Pubmed Nemet,
Submembrane assembly and renewal of rod photoreceptor cGMP-gated channel: insight into the actin-dependent process of outer segment morphogenesis.
2014,
Pubmed
,
Xenbase Nemet,
Rhodopsin Trafficking and Mistrafficking: Signals, Molecular Components, and Mechanisms.
2015,
Pubmed Nemet,
Applications of phototransformable fluorescent proteins for tracking the dynamics of cellular components.
2015,
Pubmed Nishimura,
Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin.
2004,
Pubmed Oh,
Detection of retinitis pigmentosa by differential interference contrast microscopy.
2014,
Pubmed Palczewski,
G protein-coupled receptor rhodopsin.
2006,
Pubmed Pierzyńska-Mach,
Evaluation of acridine orange, LysoTracker Red, and quinacrine as fluorescent probes for long-term tracking of acidic vesicles.
2014,
Pubmed Pôças,
2-Methoxy-3,8,9-trihydroxy coumestan: a new synthetic inhibitor of Na+,K+-ATPase with an original mechanism of action.
2003,
Pubmed Roy,
Cell-type-specific roles of Na+/K+ ATPase subunits in Drosophila auditory mechanosensation.
2013,
Pubmed Sakami,
Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations.
2011,
Pubmed Sakami,
P23H opsin knock-in mice reveal a novel step in retinal rod disc morphogenesis.
2014,
Pubmed Schneider,
Co-localization and polarized distribution of Na,K-ATPase alpha 3 and beta 2 subunits in photoreceptor cells.
1991,
Pubmed Schneider,
NIH Image to ImageJ: 25 years of image analysis.
2012,
Pubmed Simons,
Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model.
2011,
Pubmed Smith,
Xenopus laevis transgenesis by sperm nuclear injection.
2006,
Pubmed
,
Xenbase Sparrow,
A simplified method of generating transgenic Xenopus.
2000,
Pubmed
,
Xenbase Subach,
A photoswitchable orange-to-far-red fluorescent protein, PSmOrange.
2011,
Pubmed Sung,
Rhodopsin mutations responsible for autosomal dominant retinitis pigmentosa. Clustering of functional classes along the polypeptide chain.
1993,
Pubmed Sung,
A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment.
1994,
Pubmed Tam,
Identification of an outer segment targeting signal in the COOH terminus of rhodopsin using transgenic Xenopus laevis.
2000,
Pubmed
,
Xenbase Tam,
Mislocalized rhodopsin does not require activation to cause retinal degeneration and neurite outgrowth in Xenopus laevis.
2006,
Pubmed
,
Xenbase Tian,
An unconventional secretory pathway mediates the cilia targeting of peripherin/rds.
2014,
Pubmed
,
Xenbase Viczian,
Generation of functional eyes from pluripotent cells.
2009,
Pubmed
,
Xenbase Wang,
Modulators of Na/K-ATPase: a patent review.
2012,
Pubmed Wetzel,
Cellular and subcellular specification of Na,K-ATPase alpha and beta isoforms in the postnatal development of mouse retina.
1999,
Pubmed Xie,
Preparation of an activated rhodopsin/transducin complex using a constitutively active mutant of rhodopsin.
2011,
Pubmed Yamamoto,
Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells.
1998,
Pubmed Yao,
Inhibiting autophagy reduces retinal degeneration caused by protein misfolding.
2018,
Pubmed Yau,
Cyclic GMP-activated conductance of retinal photoreceptor cells.
1989,
Pubmed Young,
The renewal of photoreceptor cell outer segments.
1967,
Pubmed Zhang,
Identification of hydroxyxanthones as Na/K-ATPase ligands.
2010,
Pubmed
