The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Hirano, Kazuyuki; Zuber, Christian; Roth, Jürgen; Ziak, Martin

doi:10.1016/s0002-9440(10)63635-8

Cited by 40 publications

(38 citation statements)

References 48 publications

(65 reference statements)

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“…Consequently, mechanisms underlying subsequent degradation of the wild-type-mutant complexes of AQP2 and AE1 differ somewhat. Degradation of the dominant NDI-causing mutant E258K of AQP2 in clone 9 hepatocytes occurs rapidly in a proteasome-and lysosome-dependent manner (Hirano et al, 2003), whereas in cells transfected with the R664X mutant of AE1, the protein is principally degraded by the proteasomal pathway, as demonstrated in this study.…”

Section: Discussionsupporting

confidence: 60%

“…Mutant AQP2 molecules in dominant NDI can associate with wild-type AQP2, forming heterotetramers (Kamsteeg et al, 1999;Marr et al, 2002;Kamsteeg et al, 2003). This interaction causes retention in the Golgi complex and/or lysosomes (Mulders et al, 1998;Tamarappoo et al, 1999;Marr et al, 2002;Hirano et al, 2003) or mis-targeting of wild-type protein to the basolateral membrane (Kamsteeg et al, 2003;Asai et al, 2003), whereas AQP2 mutants in recessive NDI cannot associate with wild-type protein (Kamsteeg et al, 1999) and are retained in the ER (Deen et al, 1995;Mulders et al, 1997). Kamsteeg et al therefore suggested that AQP2 assembly into tetramers occurs after exit from the ER (Kamsteeg et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The most likely mechanism is proteolytic degradation by ER-associated degradation (ERAD) (Ellgaard and Helenius, 2003) via the proteasome pathway, as has been observed for the misfolded cystic fibrosis transmembrane-conductance regulator (CFTR) (Ward et al, 1995;Gelman et al, 2002) and certain AQP2 mutants. In the case of AQP2 mutants underlying NDI, degradation of the ERretarded AQP2 mutant T126M in recessive NDI required proteasomal activity, whereas degradation of an E258K mutant in dominant NDI occurred in a proteasome-and lysosome-dependent manner (Hirano et al, 2003). However, the contribution of proteasomal ERAD to the degradation of one AE1 mutant (R760Q) is negligible (Quilty and Reithmeier, 2000) and not entirely clear in the case of other dominant HS-associated mutants.…”

Section: Introductionmentioning

confidence: 98%

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Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle

Ito

Koshino

Arashiki

et al. 2006

Journal of Cell Science

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Various mutations in the AE1 (anion exchanger 1, band 3) gene cause dominant hereditary spherocytosis, a common congenital hemolytic anemia associated with deficiencies of AE1 of different degrees and loss of mutant protein from red blood cell membranes. To determine the mechanisms underlying decreases in AE1 protein levels, we employed K562 and HEK293 cell lines and Xenopus oocytes together with bovine wild-type AE1 and an R664X nonsense mutant responsible for dominant hereditary spherocytosis to analyze protein expression, turnover, and intracellular localization. R664X-mutant protein underwent rapid degradation and caused specifically increased turnover and impaired trafficking to the plasma membrane of the wild-type protein through hetero-oligomer formation in K562 cells. Consistent with those observations, co-expression of mutant and wild-type AE1 reduced anion transport by the wild-type protein in oocytes. Transfection studies in K562 and HEK293 cells revealed that the major pathway mediating degradation of both R664X and wild-type AE1 employed endoplasmic reticulum (ER)-associated degradation through the proteasomal pathway. Proteasomal degradation of R664X protein appeared to be independent of both ubiquitylation and N-glycosylation, and aggresome formation was not observed following proteasome inhibition. These findings indicate that AE1 R664X protein, which is associated with dominant hereditary spherocytosis, has a dominant-negative effect on the expression of wild-type AE1

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle

Ito

Koshino

Arashiki

et al. 2006

Journal of Cell Science

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“…Interestingly, some of these mutations might involve Ser256, the residue that is phosphorylated by PKA prior to enhanced accumulation of AQP2 into the apical membrane. Whereas loss of Ser256 itself results in constitutive vesicularization of AQP2 and does not result in intracellular accumulation (van Balkom et al, 2002), loss of specific residues in close proximity to Ser256, including Glu258Lys does (Hirano et al, 2003). This suggests that there might be differential regulation of the phosphorylation at Ser256, such that two different functions of the protein can be alteredmembrane accumulation subsequent to PKA activity or intracellular trafficking -depending on which interaction is disrupted.…”

Section: Discussionmentioning

confidence: 99%

Loss of calcineurin Aα results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus

Gooch

Guler

Barnes

et al. 2006

Journal of Cell Science

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The serine/threonine phosphatase calcineurin is an important signaling molecule involved in kidney development and function. One potential target of calcineurin action is the water channel aquaporin 2 (AQP2). In this study, we examined the effect of loss of calcineurin Aα (CnAα) on AQP2 function in vivo. CnAα null mice were found to have defective post-natal urine-concentrating ability and an impaired urine-concentrating response to vasopressin. Expression of AQP2 is normal but, paradoxically, vasopressin-mediated phosphorylation of the channel is decreased compared with wild-type littermates and there is no accumulation of AQP2 in the apical membrane. Calcineurin protein and activity was found in innermedullary collecting duct vesicles, and loss of calcineurin expression and activity was associated with a loss of AQP2 in the vesicle fraction. As such, the lack of vasopressin-mediated phosphorylation of AQP2 might be the result of a defect in normal trafficking of AQP2 to apical-targeted vesicles. Likewise, treatment of wild-type mice with cyclosporin A to inhibit calcineurin produces a similarly impaired urine-concentrating response to vasopressin and alterations in AQP2 phosphorylation and trafficking. These experiments demonstrate that, CnAα is required for normal intracellular trafficking of AQP2 and loss of calcineurin protein or activity disrupts AQP2 function.

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“…Recent data demonstrate that the ubiquitin-proteasome degradation system affects the activity of some membrane transporters (11)(12)(13)(14)(15)(16). The system is responsible for the disposal of many of the short-lived proteins in eukaryotic cells (17)(18)(19).…”

mentioning

confidence: 99%

Degradation of the Apical Sodium-dependent Bile Acid Transporter by the Ubiquitin-Proteasome Pathway in Cholangiocytes

Xia¹,

Roundtree²,

Merikhi³

et al. 2004

Journal of Biological Chemistry

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To attenuate injury during cholestasis, adaptive changes in bile acid transporter expression in the liver provide alternative bile acid excretory pathways. Apical sodium-dependent bile acid transporter (ASBT) (SLC10A2), only expressed in the liver on the cholangiocyte apical membrane, is rapidly regulated in response to inflammation and bile acids. Here, we studied the mechanisms controlling ASBT protein levels in cholangiocytes to determine whether ASBT expression is regulated by ubiquitination and disposal through the proteasome. Protein turnover assays demonstrated that ASBT is an unstable and short-lived protein. Treatment with MG-132, a proteasome inhibitor, causes time-dependent increased ASBT levels and increased intracellular accumulation of ASBT. In cells cotransfected with green fluorescent protein-tagged ASBT and hemagglutinin-tagged ubiquitin, we demonstrated coimmunoprecipitation and colocalization of ASBT and ubiquitin. Interleukin-1␤ (IL-1␤) induced down-regulation of ASBT is abrogated by a JNK inhibitor and is accompanied by an increase in ASBT polyubiquitin conjugates and a reduced ASBT half-life. In phosphorylation-deficient S335A and T339A mutants, the ASBT half-life is markedly prolonged, IL-1␤-induced ASBT ubiquitination is significantly reduced, and IL-1␤ fails to increase ASBT turnover. These results indicate that ASBT undergoes ubiquitin-proteasome degradation under basal conditions and that ASBT proteasome disposal is increased by IL-1␤ due to JNK-regulated serine/threonine phosphorylation of ASBT protein at both Ser-335 and Thr-339. These studies are the first report of regulation of a bile acid transporter expression by the ubiquitin-proteasome pathway.

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The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Cited by 40 publications

References 48 publications

Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle

Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle

Loss of calcineurin Aα results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus

Degradation of the Apical Sodium-dependent Bile Acid Transporter by the Ubiquitin-Proteasome Pathway in Cholangiocytes

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