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J. Biol. Chem., Vol. 280, Issue 44, 37139-37148, November 4, 2005

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Nuclear Import of B-crystallin Is Phosphorylation-dependent and Hampered by Hyperphosphorylation of the Myopathy-related Mutant R120G^*

John den Engelsman, Danny Gerrits, Wilfried W. de Jong, Jeffrey Robbins, Kanefusa Kato¶, and Wilbert C. Boelens1

From the Department of Biochemistry 161, Nijmegen Center for Molecular Life Sciences, Radboud University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands, the Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, and the ^¶Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan

Phosphorylation modulates the functioning of B-crystallin as a molecular chaperone. We here explore the role of phosphorylation in the nuclear import and cellular localization of B-crystallin in HeLa cells. Inhibition of nuclear export demonstrated that phosphorylation of B-crystallin is required for import into the nucleus. As revealed by mutant analysis, phosphorylation at Ser-59 is crucial for nuclear import, and phosphorylation at Ser-45 is required for speckle localization. Co-immunoprecipitation experiments suggested that the import of B-crystallin is possibly regulated by its phosphorylation-dependent interaction with the survival motor neuron (SMN) protein, an important factor in small nuclear ribonucleoprotein nuclear import and assembly. This interaction was supported by co-localization of endogenous phosphorylated B-crystallin with SMN in nuclear structures. The cardiomyopathy-causing B-crystallin mutant R120G was found to be excessively phosphorylated, which disturbed SMN interaction and nuclear import, and resulted in the formation of cytoplasmic inclusions. Like for other protein aggregation disorders, hyperphosphorylation appears as an important aspect of the pathogenicity of B-crystallin R120G.

Received for publication, April 15, 2005 , and in revised form, August 22, 2005.

^* This work was supported by the Netherlands Organization for Scientific Research (Grant NWO-MW 902-27-227). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tel.: 31-(0)243-616-753; Fax: 31-(0)243-540-525; E-mail: W.Boelens{at}ncmls.ru.nl.

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