Inducible nitric oxide (NO) synthase (iNOS; NOS2) produces NO and related reactive nitrogen species, which are critical effectors of the innate host response and are required for the intracellular killing of pathogens such as Mycobacterium tuberculosis and Leishmania major . We have identified SPRY domain–containing SOCS (suppressor of cytokine signaling) box protein 2 (SPSB2) as a novel negative regulator that recruits an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in its proteasomal degradation. SPSB2 interacts with the N-terminal region of iNOS via a binding interface on SPSB2 that has been mapped by nuclear magnetic resonance spectroscopy and mutational analyses. SPSB2-deficient macrophages showed prolonged iNOS expression, resulting in a corresponding increase in NO production and enhanced killing of L. major parasites. These results lay the foundation for the development of small molecule inhibitors that could disrupt the SPSB–iNOS interaction and thus prolong the intracellular lifetime of iNOS, which may be beneficial in chronic and persistent infections. Footnotes Abbreviations used in this paper: BCG Bacillus Calmette-Guérin BMDM bone marrow–derived macrophage eNOS endothelial NO synthase HSQC heteronuclear single quantum coherence iNOS inducible NO synthase ITC isothermal titration calorimetry LPS lipopolysaccharide NHS N -hydroxysuccinimide NMR nuclear magnetic resonance nNOS neuronal NO synthase NO nitric oxide RNS reactive nitrogen species SOCS suppressor of cytokine signaling Submitted: 15 December 2009 Accepted: 8 June 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
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The SPRY domain–containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation
Kuang, Zhihe; Lewis, Rowena S.; Curtis, Joan M.; Zhan, Yifan; Saunders, Bernadette M.; Babon, Jeffrey J.; Kolesnik, Tatiana B.; Low, Andrew; Masters, Seth L.; Willson, Tracy A.; Kedzierski, Lukasz; Yao, Shenggen; Handman, Emanuela; Norton, Raymond S.; Nicholson, Sandra E.
Follow The Journal of Cell Biology
, Volume 190 (1): 129
Rockefeller University Press – Jul 12, 2010
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