Biochemical and pharmacological studies have suggested that NOS2 (inducible nitric oxide synthase) has a functional role in the blood pressure response to increases in dietary salt intake. On a high-salt diet, the Dahl/Rapp salt-sensitive (S) strain of rat, a genetic model of salt-sensitive hypertension, did not show increased nitric oxide production. NOS2 from S rats possesses a point mutation that results in substitution of proline for serine at position 714. In the present study, rat NOS2 was shown to be ubiquitinated in vitro and in vivo and to be degraded by the proteasome; this process was accelerated for the S714P mutant. Accelerated degradation of the S714P mutant enzyme accounted for the diminished enzyme activity of this mutant. Hsp90 (heat-shock protein 90) associated with NOS2 and modulated degradation, but was not responsible for the accentuated degradation of the S714P mutant enzyme. The combined findings demonstrate the integral role of ubiquitination and degradation by the proteasome in the regulation of NO production by rat NOS2. Demonstrating that this process is responsible for the abnormal function of the S714P mutant NOS2 in S rats confirms the physiological importance of the proteasome in NOS2 function.
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December 2003
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Research Article|
December 15 2003
Accelerated ubiquitination and proteasome degradation of a genetic variant of inducible nitric oxide synthase
Wei-Zhong YING;
Wei-Zhong YING
*Nephrology Research and Training Center, Comprehensive Cancer Center, and Cell Adhesion and Matrix Research Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0007, U.S.A.
†Department of Veterans’ Affairs Medical Center, Birmingham, AL 35233, U.S.A.
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Paul W. SANDERS
Paul W. SANDERS
1
*Nephrology Research and Training Center, Comprehensive Cancer Center, and Cell Adhesion and Matrix Research Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0007, U.S.A.
†Department of Veterans’ Affairs Medical Center, Birmingham, AL 35233, U.S.A.
‡Department of Physiology & Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294-0007, U.S.A.
1To whom correspondence should be addressed: Division of Nephrology/Department of Medicine, 642 Lyons-Harrison Research Building, 1530 Third Avenue South, University of Alabama at Birmingham, Birmingham, AL 35294-0007, U.S.A. (e-mail psanders@uab.edu).
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Biochem J (2003) 376 (3): 789–794.
Article history
Received:
July 15 2003
Revision Received:
September 05 2003
Accepted:
September 08 2003
Accepted Manuscript online:
September 08 2003
Citation
Wei-Zhong YING, Paul W. SANDERS; Accelerated ubiquitination and proteasome degradation of a genetic variant of inducible nitric oxide synthase. Biochem J 15 December 2003; 376 (3): 789–794. doi: https://doi.org/10.1042/bj20031058
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