PDLIM5 links kidney anion exchanger 1 (kAE1) to ILK and is required for membrane targeting of kAE1

Ya, SU; Hiemstra, Thomas F.; Yan, Yahui; Li, Juan; Karet, Hannah I.; Rosen, Lawrence; Moreno, Pablo; Karet, Fiona E.

doi:10.1038/srep39701

Cited by 11 publications

(5 citation statements)

References 41 publications

(69 reference statements)

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“…The N-terminus is truncated by the first 65 amino acids present in the erythroid form of the protein, while a short C-terminus is conserved in both erythroid and renal isoforms 2 . This cytosolic domain interacts with various proteins including carbonic anhydrase II 3 , adaptor protein 1 A&B 4–6 , glyceraldehyde phosphate dehydrogenase 7 , peroxiredoxin 6 8 , and contains a putative type I PDZ binding domain 9 , which interacts with PDLIM5 10 .…”

Section: Introductionmentioning

confidence: 99%

The kidney anion exchanger 1 affects tight junction properties via claudin-4

Lashhab

Rumley

Arutyunov

et al. 2019

Sci Rep

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In the renal collecting duct, intercalated cells regulate acid-base balance by effluxing protons through the v-H + -ATPase, and bicarbonate via apical pendrin or the basolateral kidney anion exchanger 1 (kAE1). Additionally, collecting duct cells play an essential role in transepithelial absorption of sodium and chloride. Expression of kAE1 in polarized MDCK I cells was previously shown to decrease trans-epithelial electrical resistance (TEER), suggesting a novel role for kAE1 in paracellular permeability. In our study, we not only confirmed that inducible expression of kAE1 in mIMCD3 cells decreased TEER but we also observed (i) increased epithelial absolute permeability to both sodium and chloride, and (ii) that this effect was dependent on kAE1 activity. Further, kAE1 regulated tight junction properties through the tight junction protein claudin-4, a protein with which it physically interacts and colocalizes. These findings unveil a novel interaction between the junctional protein claudin-4 and the kidney anion exchanger, which may be relevant to ion and/or pH homeostasis.

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Section: Introductionmentioning

confidence: 99%

The kidney anion exchanger 1 affects tight junction properties via claudin-4

Lashhab

Rumley

Arutyunov

et al. 2019

Sci Rep

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“…It is likely that the cytosolic C‐terminal part of kAE1 induces the UPR phenotype. In mammalian cells, it is known that the cytosolic C‐terminus represents an interaction hotspot that modulates the proper transport of kAE1 to the basolateral membrane (Almomani et al, 2012; Su et al, 2011; Su et al, 2017; Toye et al, 2004). Theoretically, the mere lack of such an interaction partner required for proper folding could induce the observed accumulation and misfolding of kAE1 in yeast.…”

Section: Discussionmentioning

confidence: 99%

Boosting endoplasmic reticulum folding capacity reduces unfolded protein response activation and intracellular accumulation of human kidney anion exchanger 1 in Saccharomyces cerevisiae

Cordat

Becker

2021

Yeast

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Human kidney anion exchanger 1 (kAE1) facilitates simultaneous efflux of bicarbonate and absorption of chloride at the basolateral membrane of α‐intercalated cells. In these cells, kAE1 contributes to systemic acid–base balance along with the proton pump v‐H+‐ATPase and the cytosolic carbonic anhydrase II. Recent electron microscopy analyses in yeast demonstrate that heterologous expression of several kAE1 variants causes a massive accumulation of the anion transporter in intracellular membrane structures. Here, we examined the origin of these kAE1 aggregations in more detail. Using various biochemical techniques and advanced light and electron microscopy, we showed that accumulation of kAE1 mainly occurs in endoplasmic reticulum (ER) membranes which eventually leads to strong unfolded protein response (UPR) activation and severe growth defect in kAE1 expressing yeast cells. Furthermore, our data indicate that UPR activation is dose dependent and uncoupled from the bicarbonate transport activity. By using truncated kAE1 variants, we identified the C‐terminal region of kAE1 as crucial factor for the increased ER stress level. Finally, a redistribution of ER‐localized kAE1 to the cell periphery was achieved by boosting the ER folding capacity. Our findings not only demonstrate a promising strategy for preventing intracellular kAE1 accumulation and improving kAE1 plasma membrane targeting but also highlight the versatility of yeast as model to investigate kAE1‐related research questions including the analysis of structural features, protein degradation and trafficking. Furthermore, our approach might be a promising strategy for future analyses to further optimize the cell surface targeting of other disease‐related PM proteins, not only in yeast but also in mammalian cells.

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“…It has been shown that the PDZ domain of PDLIM5 interacts with α-actinin in cardiomyocytes [30]. PDLIM5 also acts as a direct binding partner for Anion exchanger 1 (AE1) via its PDZ domain for membrane targeting [50]. Determining how and which PDZ protein family members specify nAChRs expression, localization, and activity will be an important part of understanding the nature of nicotinic signaling.…”

Section: Discussionmentioning

confidence: 99%

A Novel Effect of PDLIM5 In α7 Nicotinic Acetylcholine Receptors Up-Regulation And Surface Expression

Li¹,

Gou²,

Wang³

et al. 2021

Preprint

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α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are expressed widely in the brain, where they contribute to a variety of behaviors including arousal and cognition, participate in a number of neurodegenerative disorders including Alzheimer’s and Parkinson’s disease, and is responsible for nicotine addiction. Although recent studies indicate that the PDZ-containing proteins comprising PSD-95 family co-localize with nicotinic acetylcholine receptors and mediate downstream signaling in the neurons, the mechanisms by which α7nAChRs are regulated are still less well understood. Here we show that the regulation of the α7nAChRs is controlled by PDLIM5 in the endogenous PDZ domain proteins family. We find that chronic exposure to 1 μM nicotine up-regulated both α7, β2-contained nAChRs and PDLIM5 in primary cultured hippocampal neurons, and the up-regulation of α7nAChRs and PDLIM5 is increased more on the cell membrane than the cytoplasm. Interestingly, the α7nAChRs and β2nAChRs display distinct patterns of expression, with α7 co-localized more with PDLIM5. Meanwhile, PDLIM5 interacts with native brain α7 but not β2 nAChRs in neurons. Moreover, knocking down of PDLIM5 in heterologous cells abolishes nicotine-induced up-regulation of α7nAChRs. In cultured hippocampal neurons, shRNA against PDLIM5 decreased both surface clustering of α7nAChRs and α7nAChRs mediated currents. Proteomics analysis shows PDLIM5 interacts with α7nAChRs through the PDZ domain and the interaction between PDLIM5 and α7nAChRs can be promoted by nicotine. Collectively, our data suggest a novel cellular role of PDLIM5 in regulating α7nAChRs, which may be relevant to plastic changes in the nervous system.

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PDLIM5 links kidney anion exchanger 1 (kAE1) to ILK and is required for membrane targeting of kAE1

Cited by 11 publications

References 41 publications

The kidney anion exchanger 1 affects tight junction properties via claudin-4

The kidney anion exchanger 1 affects tight junction properties via claudin-4

Boosting endoplasmic reticulum folding capacity reduces unfolded protein response activation and intracellular accumulation of human kidney anion exchanger 1 in Saccharomyces cerevisiae

A Novel Effect of PDLIM5 In α7 Nicotinic Acetylcholine Receptors Up-Regulation And Surface Expression

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