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LIP5 Interacts with Aquaporin 2 and Facilitates Its Lysosomal Degradation

Bas W.M. van Balkom^*, Michelle Boone^*, Giel Hendriks, Erik-Jan Kamsteeg^*, Joris H. Robben^*, H. Christiaan Stronks^*, Anne van der Voorde, Francois van Herp^,||, Peter van der Sluijs and Peter M.T. Deen^*

Departments of ^* Physiology and Molecular Animal Physiology, Nijmegen Center of Molecular Sciences, and ^|| Donders Center for Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, and Department of Cell Biology, University Medical Center Utrecht, Utrecht, Netherlands

Correspondence: Dr. Peter M.T. Deen, 286 Department Physiology, UMC Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, Netherlands. Phone: 31-24-3617347; Fax: 31-24-3616413; E-mail: p.deen{at}ncmls.ru.nl

Received for publication June 26, 2008. Accepted for publication December 7, 2008.

Vasopressin binding to the V2 receptor in renal principal cells leads to activation of protein kinase A, phosphorylation of aquaporin 2 (AQP2) at Ser256, and the translocation of AQP2 to the apical membrane, resulting in concentration of the urine. In contrast, phorbol ester–induced activation of protein kinase C pathway leads to ubiquitination of AQP2 at Lys270 and its internalization to multivesicular bodies, where it is targeted for lysosomal degradation or stored for recycling. Because little is known about the regulation of AQP2 trafficking, we used the carboxy-terminal tail of constitutively nonphosphorylated AQP2 (S256A) as a bait for interacting proteins in a yeast two-hybrid assay. We isolated lysosomal trafficking regulator–interacting protein 5 (LIP5) and found that LIP5 interacted with the proximal carboxy-terminal tail (L230-D243) of AQP2 in vitro but not with AQP3 or AQP4, which are also expressed in principal cells. Immunohistochemistry revealed that LIP5 co-localized with AQP2 in principal cells. LIP5 binding occurred independent of the state of Ser256 phosphorylation or Lys270 ubiquitination. LIP5 has been shown to facilitate degradation of the EGF receptor; here, LIP5 seemed to bind this receptor. Knockdown of LIP5 in mouse renal cells (mpkCCD) reduced the phorbol ester–induced degradation of AQP2 approximately two-fold. In summary, LIP5 binds cargo proteins and, considering the role of LIP5 in protein sorting to multivesicular bodies, plays a role in the degradation of AQP2, possibly by reducing the formation of late endosomes.

This article has been cited by other articles:

				H. B. Moeller, J. Praetorius, M. R. Rutzler, and R. A. Fenton Phosphorylation of aquaporin-2 regulates its endocytosis and protein-protein interactions PNAS, January 5, 2010; 107(1): 424 - 429. [Abstract] [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673