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J. Biol. Chem., Vol. 283, Issue 28, 19283-19292, July 11, 2008

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Phosphoinositides Suppress -Secretase in Both the Detergent-soluble and -insoluble States^*

Satoko Osawa¹, Satoru Funamoto², Mika Nobuhara, Satoko Wada-Kakuda³, Masafumi Shimojo^¶, Sosuke Yagishita^||, and Yasuo Ihara

From the Department of Neuropathology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, the Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto610-0394, Japan, the ^¶Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, and the ^||Department of Life Science, Graduate School of Arts and Science, The University of Tokyo, Tokyo 153-8902, Japan

-Secretase is an aspartic protease that hydrolyzes type I membrane proteins within the hydrophobic environment of the lipid bilayer. Using the CHAPSO-solubilized -secretase assay system, we previously found that -secretase activity was sensitive to the concentrations of detergent and phosphatidylcholine. This strongly suggests that the composition of the lipid bilayer has a significant impact on the activity of -secretase. Recently, level of secreted β-amyloid protein was reported to be attenuated by increasing levels of phosphatidylinositol 4,5-diphosphate (PI(4,5)P₂) in cultured cells. However, it is not clear whether PI(4,5)P₂ has a direct effect on -secretase activity. In this study, we found that phosphoinositides directly inhibited CHAPSO-solubilized -secretase activity. Interestingly, neither phosphatidylinositol nor inositol triphosphate altered -secretase activity. PI(4,5)P₂ was also found to inhibit -secretase activity in CHAPSO-insoluble membrane microdomains (rafts). Kinetic analysis of β-amyloid protein production in the presence of PI(4,5)P₂ suggested a competitive inhibition. Even though phosphoinositides are minor phospholipids of the membrane, the concentration of PI(4,5)P₂ within the intact membrane has been reported to be in the range of 4–8 mM. The presence of PI(4,5)P₂-rich rafts in the membrane has been reported in a range of cell types. Furthermore, -secretase is enriched in rafts. Taking these data together, we propose that phosphoinositides potentially regulate -secretase activity by suppressing its association with the substrate.

Received for publication, July 20, 2007 , and in revised form, May 5, 2008.

^* This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Area-Research on Pathomechanisms of Brain Disorders (to Y. I.), by a Grant-in-Aid for Scientific Research on Encouragement of Young Scientists (A) (to S. F.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, by funding from the Public Health Research Foundation (to S. F.), and by funding from the Uehara Memorial Foundation (to S. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Present address: Dept. of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

³ Present address: Dept. of Neurology, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan.

² To whom correspondence should be addressed: Dept. of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan. Tel.: 81-774-65-6136; Fax: 81-774-65-6135; E-mail: sfunamot{at}mail.doshisha.ac.jp.

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