LIP5 Interacts with Aquaporin 2 and Facilitates Its Lysosomal Degradation

Balkom, Bas W. M. van; Boone, Michelle; Hendriks, Giel; Kamsteeg, Erik‐Jan; Robben, Joris H.; Stronks, H. Christiaan; Voorde, Anne van der; Herp, F. Van; Sluijs, Peter van der; Deen, Peter M.T.

doi:10.1681/asn.2008060648

Cited by 48 publications

(54 citation statements)

References 59 publications

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“…The mutants S256D and S269D had a significantly longer halflife compared to WT-AQP2. From our studies, we cannot determine whether the decreased degradation of 256D-and 269D-AQP2 is due to their decreased internalization and subsequently reduced sorting to the proteolytic pathway or due to a more direct effect such as reduced sorting to the proteolytic pathways via reduced protein-protein interactions; e.g., LIP5 interacts with the COOH-terminal tail of AQP2 (17). In contrast, mutating S264 to either alanine or aspartate resulted in increased AQP2 protein half-life, without significant effects on protein trafficking, suggesting, as previously (6), a more direct role of this residue in sorting AQP2 following endocytic retrieval.…”

Section: Phosphorylation Of Aqp2 Regulates Both Its Endocytosis and Itsmentioning

confidence: 94%

Phosphorylation of aquaporin-2 regulates its endocytosis and protein–protein interactions

Moeller

Prætorius

Rützler

et al. 2009

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

160

166

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The water channel aquaporin-2 (AQP2) is essential for urine concentration. Vasopressin regulates phosphorylation of AQP2 at four conserved serine residues at the COOH-terminal tail (S256, S261, S264, and S269). We used numerous stably transfected Madin-Darby canine kidney cell models, replacing serine residues with either alanine (A), which prevents phosphorylation, or aspartic acid (D), which mimics the charged state of phosphorylated AQP2, to address whether phosphorylation is involved in regulation of (i) apical plasma membrane abundance of AQP2, (ii) internalization of AQP2, (iii) AQP2 protein-protein interactions, and (iv) degradation of AQP2. Under control conditions, S256D-and 269D-AQP2 mutants had significantly greater apical plasma membrane abundance compared to wild type (WT)-AQP2. Activation of adenylate cyclase significantly increased the apical plasma membrane abundance of all S-A or S-D AQP2 mutants with the exception of 256D-AQP2, although 256A-, 261A-, and 269A-AQP2 mutants increased to a lesser extent than WT-AQP2. Biotin internalization assays and confocal microscopy demonstrated that the internalization of 256D-and 269D-AQP2 from the plasma membrane was slower than WT-AQP2. The slower internalization corresponded with reduced interaction of S256D-and 269D-AQP2 with several proteins involved in endocytosis, including Hsp70, Hsc70, dynamin, and clathrin heavy chain. The mutants with the slowest rate of internalization, 256D-and 269D-AQP2, had a greater protein half-life (t 1/2 = 5.1 h and t 1/2 = 4.4 h, respectively) compared to WT-AQP2 (t 1/2 = 2.9 h). Our results suggest that vasopressin-mediated membrane accumulation of AQP2 can be controlled via regulated exocytosis and endocytosis in a process that is dependent on COOH terminal phosphorylation and subsequent protein-protein interactions.Madin-Darby canine kidney cells | trafficking | vasopressin | water homeostasis | water channel A quaporin-2 (AQP2) is a water-channel protein expressed in the collecting duct of the kidney. Following increased vasopressin (AVP) levels, shuttling and fusion of AQP2 vesicles to the apical plasma membrane lead to water absorption and urine concentration. Knepper and Nielsen proposed that the plasma membrane abundance of AQP2 is a regulated balance between endocytosis and exocytosis (1). The downstream effects of the AVP-mediated signaling cascade on AQP2 exocytosis are complex and involve activation of adenylate cyclase, increased cAMP and intracellular Ca 2+ levels, and increased protein kinase A (PKA) activation. Additionally, both nitric oxide and atrial naturetic peptide, known to increase cGMP levels, can induce apical AQP2 accumulation (2). Currently, little is known about the process of AQP2 endocytosis, although it has been reported that both prostaglandin E2 and dopamine can induce AQP2 internalization (3) and that AQP2 ubiquitination is also involved (4).AVP regulates the phosphorylation of four residues in the carboxyl terminal tail of AQP2 at positions S256, S261, S264, and S269 (5-7). S256 phospho...

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Section: Phosphorylation Of Aqp2 Regulates Both Its Endocytosis and Itsmentioning

confidence: 94%

Phosphorylation of aquaporin-2 regulates its endocytosis and protein–protein interactions

Moeller

Prætorius

Rützler

et al. 2009

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

160

166

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“…10 The extension of monoubiquitin by two or three additional ubiquitin moieties (short-chain ubiquitination) apparently participates in the control of AQP2 degradation. 10,11 pUb of AQP2 has not been observed. The signaling processes controlling ubiquitination, and therefore the AQP2 abundance, are largely unknown.…”

mentioning

confidence: 85%

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Nedvetsky

Tabor

Tamma

et al. 2010

Journal of the American Society of Nephrology

106

129

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Arginine-vasopressin (AVP) modulates the water channel aquaporin-2 (AQP2) in the renal collecting duct to maintain homeostasis of body water. AVP binds to vasopressin V2 receptors (V2R), increasing cAMP, which promotes the redistribution of AQP2 from intracellular vesicles into the plasma membrane. cAMP also increases AQP2 transcription, but whether altered degradation also modulates AQP2 protein levels is not well understood. Here, elevation of cAMP increased AQP2 protein levels within 30 minutes in primary inner medullary collecting duct (IMCD) cells, in human embryonic kidney (HEK) 293 cells ectopically expressing AQP2, and in mouse kidneys. Accelerated transcription or translation did not explain this increase in AQP2 abundance. In IMCD cells, cAMP inhibited p38-mitogen-activated protein kinase (p38-MAPK) via activation of protein kinase A (PKA). Inhibition of p38-MAPK associated with decreased phosphorylation (serine 261) and polyubiquitination of AQP2, preventing proteasomal degradation. Our results demonstrate that AVP enhances AQP2 protein abundance by altering its proteasomal degradation through a PKA-and p38-MAPK-dependent pathway. Aquaporin-2 (AQP2) is the water channel mediating arginine-vasopressin (AVP)-increases in water re-absorption in renal collecting duct principal cells. 1-4 AVP binds to plasma membrane-located vasopressin V2 receptors, thereby stimulating adenylyl cyclase and elevating cAMP. cAMP activates protein kinase A (PKA), which phosphorylates AQP2 at serine 256 (S256), inducing its redistribution from intracellular vesicles into the plasma membrane. 3,4 This short-term regulation of AQP2 occurs within seconds to minutes. In the case of long-term regulation, cAMP enhances AQP2 mRNA expression, followed by a rise in the AQP2 protein level within hours. 5,6 AQP2 can be degraded in proteasomes and lysosomes. 7,8 Ubiquitination directs proteins for degradation to both compartments. Monoubiquitination (mUb) is a signal for degradation in lysosomes, whereas polyubiquitination (pUb) is mainly linked to proteasomal degradation. 9 mUb of AQP2 is induced by FSK stimulation and occurs at the apical plasma membrane. 10 In WT5 cells, a model for AQP2 regulation, increased mUb of AQP2 persists

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“…A protein involved in MVB formation is the lysosomal trafficking regulator interacting protein 5 (LIP5). LIP5 is abundantly expressed in the collecting duct (45) and has been shown to interact with AQP2 and facilitate its lysosomal degradation (46).…”

Section: Camentioning

confidence: 99%

X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking

Frick

Eriksson

Mattia

et al. 2014

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

130

111

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Human aquaporin 2 (AQP2) is a water channel found in the kidney collecting duct, where it plays a key role in concentrating urine. Water reabsorption is regulated by AQP2 trafficking between intracellular storage vesicles and the apical membrane. This process is tightly controlled by the pituitary hormone arginine vasopressin and defective trafficking results in nephrogenic diabetes insipidus (NDI). Here we present the X-ray structure of human AQP2 at 2.75 Å resolution. The C terminus of AQP2 displays multiple conformations with the C-terminal α-helix of one protomer interacting with the cytoplasmic surface of a symmetry-related AQP2 molecule, suggesting potential protein-protein interactions involved in cellular sorting of AQP2. Two Cd 2+ -ion binding sites are observed within the AQP2 tetramer, inducing a rearrangement of loop D, which facilitates this interaction. The locations of several NDI-causing mutations can be observed in the AQP2 structure, primarily situated within transmembrane domains and the majority of which cause misfolding and ER retention. These observations provide a framework for understanding why mutations in AQP2 cause NDI as well as structural insights into AQP2 interactions that may govern its trafficking.membrane protein | X-ray crystallography | water channel protein W ater is the major ingredient of the human body, constituting 55-65% of our total body weight (1). Water homeostasis is maintained by the kidneys, which filter ∼180 L of primary urine every day. Although most water is constitutively reabsorbed in the proximal tubules and descending limbs of Henle (2), the body's water balance is fine-tuned by regulated water reabsorption, which takes place in the kidney collecting duct. Water reabsorption is mediated by aquaporins, membranebound water channels, of which seven of the 13 human isoforms have been located in the human kidney (3). Of these, human aquaporin 2 (AQP2) is present in the principal cells of the collecting duct and is responsible for regulated water reabsorption.AQP2 is stored in intracellular vesicles under water-saturating conditions. When the levels of the pituitary antidiuretic hormone arginine vasopressin (AVP) are elevated in response to dehydration or hypernatremia, AVP binding to the vasopressin 2 receptor (V2R) in the basolateral membrane stimulates an increase in intracellular cAMP. This triggers the phosphorylation of Ser256 in the AQP2 C terminus by protein kinase A (PKA) and flags the protein for trafficking from storage vesicles to the apical membrane (4-6). AVP also triggers additional phosphorylation at Ser264 and Ser269 (7,8), with all three sites being phosphorylated in AQP2s targeted to the plasma membrane (9). The resulting redistribution of AQP2 increases transcellular water permeability and concentrates urine (Fig. S1). Once correct water balance is restored, AQP2 is internalized through ubiquitinmediated endocytosis and redirected to storage vesicles or targeted for degradation (10-12).Because of its central role in water homeostasis, dysregula...

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LIP5 Interacts with Aquaporin 2 and Facilitates Its Lysosomal Degradation

Cited by 48 publications

References 59 publications

Phosphorylation of aquaporin-2 regulates its endocytosis and protein–protein interactions

Phosphorylation of aquaporin-2 regulates its endocytosis and protein–protein interactions

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking

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