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J. Biol. Chem., Vol. 281, Issue 25, 16861-16869, June 23, 2006

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The Ubiquitin-like Protein MNSF Regulates ERK-MAPK Cascade^*

Morihiko Nakamura¹ and Seiji Yamaguchi

From the Department of Cooperative Medical Research, Collaboration Center, and the Department of Pediatrics, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan

MNSF is a ubiquitously expressed member of the ubiquitin-like family that has been implicated in various biological functions. Previous studies have demonstrated that MNSF covalently binds to intracellular proapoptotic protein Bcl-G in mitogen-activated murine T cells. In this study, we further investigated the intracellular mechanism of action of MNSF in macrophage cell line, Raw 264.7 cells. We present evidence that MNSF·Bcl-G complex associates with ERKs in non-stimulated Raw 264.7. We found that MNSF·Bcl-G directly bound to ERKs and inhibited ERK activation by MEK1. In Raw 264.7 cells treated with MNSF small interfering RNA (siRNA) lipopolysaccharide (LPS)-induced ERK1/2 activation was enhanced and LPS-induced JNK and p38 activation was unaffected. SiRNA-mediated knockdown of MNSF increased tumor necrosis factor (TNF) expression at mRNA and protein levels in LPS-stimulated Raw 264.7 cells. Finally, we found that transfection with MNSF expression construct resulted in a significant inhibition of LPS-induced ERK activation and TNF production. Co-transfection experiments with MNSF and Bcl-G greatly enhanced this inhibition. Collectively, these findings indicate that MNSF might be implicated in the macrophage response to LPS.

Received for publication, September 8, 2005 , and in revised form, April 3, 2006.

^* 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.: 81-853-20-2916; Fax: 81-853-20-2913; E-mail: nkmr0515{at}med.shimane-u.ac.jp.

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