Ubiquitin-like protein MNSF? covalently binds to Bcl-G and enhances lipopolysaccharide/interferon ?-induced apoptosis in macrophages.

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Ubiquitin-like protein MNSF? covalently binds to Bcl-G and enhances lipopolysaccharide/interferon ?-induced apoptosis in macrophages.

FEBS J. 2013 Mar;280(5):1281-93

Authors: Watanabe J, Nakagawa M, Watanabe N, Nakamura M

Abstract
Monoclonal non-specific suppressor factor ? (MNSF?) is a ubiquitously expressed member of the ubiquitin-like family that is involved in various biological functions. Previous studies have demonstrated that MNSF? covalently binds to intracellular pro-apoptotic protein Bcl-G and regulates the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade in the mouse macrophage cell line Raw264.7. In this study, we demonstrate that MNSF? promotes lipopolysaccharide (LPS)/interferon ? (IFN?)-induced apoptosis of Raw264.7 macrophages. In Raw264.7 cells treated with MNSF? small interfering RNA (siRNA), LPS/IFN?- or NO donor S-nitrosoglutathione-induced apoptosis was inhibited. siRNA-mediated knockdown of MNSF? did not affect inducible nitric-oxide synthase (iNOS) expression in LPS/IFN?-stimulated Raw264.7 cells. Conversely, co-transfection with MNSF? and Bcl-G greatly enhanced LPS/IFN?- induced apoptosis in Raw264.7 cells, accompanied by increased expression of p53 and decreased Cox-2 activity. Unlike co-transfection with wild-type MNSF?, co-transfection of a mutant MNSF? (G74A) and Bcl-G did not result in enhancement of LPS/IFN?-induced apoptosis. Co-over-expression of MNSF? and Bcl-G reduced S-nitrosoglutathione-induced ERK1/2 phosphorylation. Furthermore, electrophoretic mobility shift assay experiments revealed that MNSF? down-regulates the ERK/activator protein 1 (AP-1) signaling cascade which leads to Cox-2 activation. We also observed that MNSF?-Bcl-G promotes LPS/IFN?-induced apoptosis of mouse peritoneal macrophages, together with a decrease in Cox-2 expression. Taken together, our data indicate an apoptosis-enhancing effect of MNSF?-Bcl-G is due in part to down-regulation of Cox-2 activation in macrophages.

PMID: 23298187 [PubMed - indexed for MEDLINE]

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