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J. Biol. Chem., Vol. 282, Issue 11, 7973-7981, March 16, 2007

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The Microtubule-binding Protein Hook3 Interacts with a Cytoplasmic Domain of Scavenger Receptor A^*

Hitomi Sano¹, Masaho Ishino^¶, Helmut Krämer^||2, Takeyuki Shimizu, Hiroaki Mitsuzawa, Chiaki Nishitani, and Yoshio Kuroki

From the Departments of Biochemistry and ^¶Hygiene, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan, the ^||Center for Basic Neuroscience and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

The class A scavenger receptor (SR-A) is a multifunctional transmembrane glycoprotein that is implicated in atherogenesis, innate immunity, and cell adhesion. Despite extensive structure-function studies of the receptor, intracellular molecules that directly interact with SR-A and regulate the receptor trafficking have not been determined. In the current study, we have identified a microtubule-binding protein, Hook3, as a novel interacting partner of SR-A. The association between a rat Hook3 isoform and SR-A was suggested by yeast two-hybrid screening and mass spectrometry analysis of SR-A-cytoplasmic domain-bound proteins in rat alveolar macrophages. The binding of overexpressed and endogenous human Hook3 to SR-A was demonstrated by pull-down assay and co-immunoprecipitations. Furthermore, endogenous murine SR-A and HK3 co-sedimented from cell lysates isolated from Raw264.7 murine macrophage cells. The interaction of Hook3 with SR-A was significantly stimulated after SR-A had recognized the extracellular ligand. Studies using truncations demonstrated that the positively charged C-terminal Val⁶¹⁴–Ala⁷¹⁷ region of human Hook3 was required for the interaction with the negatively charged residues, Glu¹², Asp¹³, and Asp¹⁵ in the human SR-A cytoplasmic domain. By transfecting small interfering RNA targeting Hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of SR-A were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that Hook3 may participate in the turnover of the endocytosed scavenger receptor.

Received for publication, December 18, 2006

^* This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture, Japan, and the Akiyama Foundation. 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.

² Supported by Welch Foundation Grant I-1300 and National Institutes of Health Grant NS43406.

¹ To whom correspondence should be addressed: South-1 West-17, Chuo-ku, Sapporo 060-8556, Japan. Tel.: 81-11-611-2111; Fax: 81-11-611-2236; E-mail: sanohito{at}sapmed.ac.jp.

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