Association with β-COP Regulates the Trafficking of the Newly Synthesized Na,K-ATPase*

Morton, Michael J.; Farr, Glen A.; Hull, Michael; Capendeguy, Oihana; Horisberger, Jean‐Daniel; Caplan, Michael J.

doi:10.1074/jbc.m110.141119

Cited by 14 publications

(13 citation statements)

References 30 publications

(25 reference statements)

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“…To test if this region is involved in setting the differential localization, a set of chimeras with this region exchanged were analyzed. GFP‐α3 /α4 and GFP‐α4 /α3, were localized in patterns opposite to that of the parent constructs demonstrating that the targeting information lies within the intrinsically disordered region (Figure A,B). A subsequent pair of chimeras with only 24 amino acids substituted, GFP‐α3 /α4 and GFP‐α4 /α3, was generated and found to also have reversed localization patterns compared with the parent constructs (Figure C,D).…”

Section: Resultsmentioning

confidence: 96%

Identification of a VxP Targeting Signal in the Flagellar Na⁺/K⁺‐ATPase

Laird

Pan

Modestou

et al. 2015

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Na+/K+-ATPase (NKA) participates in setting electrochemical gradients, cardiotonic steroid signaling, and cellular adhesion. Distinct isoforms of NKA are found in different tissues and subcellular localization patterns. For example, NKA α1 is widely expressed, NKA α3 is enriched in neurons, and NKA α4 is a testes specific isoform found in sperm flagella. In some tissues, ankyrin, a key component of the membrane cytoskeleton, can regulate the trafficking of NKA. In the retina, NKA and ankyrin-B are expressed in multiple cell types and immunostaining for each is striking in the synaptic layers. Labeling for NKA is also prominent along the inner segment plasma membrane of photoreceptors. NKA co-immunoprecipitates with ankyrin-B, but on a subcellular level co-localization of these two proteins varies dependent on the cell type. We used transgenic X. laevis tadpoles to evaluate the subcellular trafficking of NKA in photoreceptors. GFP-NKA α3 and α1 localized to the inner segment plasma membrane, but α4 localized to outer segments. We identified a VxP motif responsible for the outer segment targeting by using a series of chimeric and mutant NKA constructs. This motif is similar to previously identified ciliary targeting motifs. Given the structural similarities between outer segments and flagella, our findings shed light on the subcellular targeting of this testes specific NKA isoform.

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Section: Resultsmentioning

confidence: 96%

Identification of a VxP Targeting Signal in the Flagellar Na⁺/K⁺‐ATPase

Laird

Pan

Modestou

et al. 2015

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“…Using APP biotinylation assays, we previously showed that δ-COP silencing dramatically decreased the amount of APP at the cell surface (3). Here we demonstrated that this effect was relatively specific for APP as the amount of Notch [gammasecretase substrate that has a half-life comparable to APP (10,11)], two other cargo proteins of the COPI complex (NMDAR and Na,K-ATPase) (12,13), as well as two resident proteins of the cell surface (E-cadherin and syndecan) were unchanged ( Fig. 1 E and F).…”

Section: Significancementioning

confidence: 82%

Relevance of the COPI complex for Alzheimer’s disease progression in vivo

Bettayeb

Hooli

Parrado

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cellular trafficking and recycling machineries belonging to late secretory compartments have been associated with increased Alzheimer's disease (AD) risk. We have shown that coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-toendoplasmic reticulum retrograde transport, affects amyloid precursor protein subcellular localization, cell-surface expression, as well as its metabolism. We present here a set of experiments demonstrating that, by targeting subunit δ-COP function, the moderation of the COPI-dependent trafficking in vivo leads to a significant decrease in amyloid plaques in the cortex and hippocampus of neurological 17 mice crossed with the 2xTg AD mouse model. Remarkably, an improvement of the memory impairments was also observed. Importantly, human genetic association studies of different AD cohorts led to the identification of 12 SNPs and 24 mutations located in COPI genes linked to an increased AD risk. These findings further demonstrate in vivo the importance of early trafficking steps in AD pathogenesis and open new clinical perspectives.ne of the hallmarks of Alzheimer's disease (AD) is the accumulation of Aβ peptides that aggregate over time to form oligomers and lead ultimately to amyloid plaques. Aβ peptides result from cleavages of the amyloid precursor protein (APP) that occur sequentially (1) and concomitantly with APP trafficking, mainly from the plasma membrane to late endosomes (1, 2). We recently addressed the possible involvement of early trafficking steps and demonstrated that at least one subunit of coat protein complex I (COPI), the main machinery underlying the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER), regulates APP trafficking, controlling its maturation and consequently the production of Aβ peptides (3). These biochemical and cellular findings demonstrate the physiological relevance of the COPI complex in AD. All together, these results indicate that the origin of the increased Aβ production in pathological conditions, when trafficking through the endocytic pathway, might be due to APP maturation-state impairments.Moreover, an in vivo model of impairment in COPI subunit delta (δ-COP), the neurological 17 (Nur17) mouse, was previously developed (4) but not yet studied in the context of AD. This mouse model represents a valuable and unique tool to characterize the relevance of δ-COP in AD etiology. The Nur17 mouse was generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, and positional cloning revealed that it carries a T-to-C missense mutation in δ-COP, leading to partial disruption of intracellular trafficking.Further highlighting the important role of trafficking in regulating Aβ production, in genome-wide association studies (GWASs) essential components of cellular trafficking and recycling involved in the endocytic or retromer pathways (endosometo-Golgi retrieval) have been found to be associated with increased AD risk (5, 6).In our previous study identifying δ-COP as a key regulator of APP biology (3), we demonstra...

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Section: Namentioning

confidence: 99%

“…Recently, it has been shown in COS cells that the Na pump asubunit physically interacts with b-coatomer protein (b-COP) shortly after translation and threading into the ER, and is targeted for degradation (Morton et al, 2010). In order to 'rescue' the asubunit from ER degradation, its interactions with b-COP must be replaced with an association between the Na pump a-and bsubunits (Morton et al, 2010). Interestingly, we observed that not only was a-b assembly required for proper trafficking of the complex, but that assembly immediately produced a significant ouabain-sensitive Na pump in ER microsomes (Gatto et al, 2001).…”

Section: Namentioning

confidence: 99%

Nuclear Na,K-ATPase plays an active role in Nucleoplasmic Calcium Homeostasis*

Galva

Artigas

Gatto

2012

Journal of Cell Science

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Summary Na + /K + -ATPase, an integral membrane protein, has been studied for over a half century with respect to its transporter function in the plasma membrane, where it expels three Na + ions from the cell in exchange for two K + ions. In this study, we demonstrate a functioning Na + /K + -ATPase within HEK293 cell nuclei. This subcellular localization was confirmed by western blotting, ouabain-sensitive ATPase activity of the nuclear membrane fraction, immunocytochemistry and delivery of fluorescently tagged Na + /K + -ATPase a-and bsubunits. In addition, we observed an overlap between nuclear Na + /K + -ATPase and Na/Ca-exchanger (NCX) when nuclei were immunostained with commercially available Na + /K + -ATPase and NCX antibodies, suggesting a concerted physiological coupling between these transporters. In keeping with this, we observed an ATP-dependent, strophanthidin-sensitive Na + flux into the nuclear envelope (NE) lumen loaded with the Na-sensitive dye, CoroNa-Green. Analogous experiments using Fluo-5N, a low affinity Ca 2+ indicator, demonstrated a similar ATP-dependent and strophanthidin-sensitive Ca 2+ flux into the NE lumen. Our results reveal an intracellular physiological role for the coordinated efforts of the Na + /K + -ATPase and NCX to actively remove Ca 2+ from the nucleoplasm into the NE lumen (i.e. the nucleoplasmic reticulum).

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Association with β-COP Regulates the Trafficking of the Newly Synthesized Na,K-ATPase*

Cited by 14 publications

References 30 publications

Identification of a VxP Targeting Signal in the Flagellar Na⁺/K⁺‐ATPase

Identification of a VxP Targeting Signal in the Flagellar Na⁺/K⁺‐ATPase

Relevance of the COPI complex for Alzheimer’s disease progression in vivo

Nuclear Na,K-ATPase plays an active role in Nucleoplasmic Calcium Homeostasis*

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Association with β-COP Regulates the Trafficking of the Newly Synthesized Na,K-ATPase*

Cited by 14 publications

References 30 publications

Identification of a VxP Targeting Signal in the Flagellar Na+/K+‐ATPase

Identification of a VxP Targeting Signal in the Flagellar Na+/K+‐ATPase

Relevance of the COPI complex for Alzheimer’s disease progression in vivo

Nuclear Na,K-ATPase plays an active role in Nucleoplasmic Calcium Homeostasis*

Contact Info

Product

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Identification of a VxP Targeting Signal in the Flagellar Na⁺/K⁺‐ATPase

Identification of a VxP Targeting Signal in the Flagellar Na⁺/K⁺‐ATPase