Format

Send to

Choose Destination
J Cell Biol. 2010 Jul 12;190(1):129-41. doi: 10.1083/jcb.200912087. Epub 2010 Jul 5.

The SPRY domain-containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation.

Author information

1
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.

Abstract

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.

PMID:
20603330
PMCID:
PMC2911665
DOI:
10.1083/jcb.200912087
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center