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

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.

SUBMITTER: Kuang Z

PROVIDER: S-EPMC2911665 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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

Kuang Zhihe Z Lewis Rowena S RS Curtis Joan M JM Zhan Yifan Y Saunders Bernadette M BM Babon Jeffrey J JJ Kolesnik Tatiana B TB Low Andrew A Masters Seth L SL Willson Tracy A TA Kedzierski Lukasz L Yao Shenggen S Handman Emanuela E Norton Raymond S RS Nicholson Sandra E SE

The Journal of cell biology 20100705 1

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 pro ...[more]

PMID: 20603330

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Project description:BackgroundLamins are major structural proteins of the nucleus and contribute to the organization of various nuclear functions. Mutations in the human lamin A gene cause a number of highly degenerative diseases, collectively termed as laminopathies. Cells expressing lamin mutations exhibit abnormal nuclear morphology and altered heterochromatin organization; however, the mechanisms responsible for these defects are not well understood.Methodology and principal findingsThe lamin A rod domain mutants G232E, Q294P and R386K are either diffusely distributed or form large aggregates in the nucleoplasm, resulting in aberrant nuclear morphology in various cell types. We examined the effects of these lamin mutants on the distribution of heterochromatin protein 1 (HP1) isoforms. HeLa cells expressing these mutants showed a heterogeneous pattern of HP1alpha and beta depletion but without altering HP1gamma levels. Changes in HP1alpha and beta were not observed in cells expressing wild-type lamin A or mutant R482L, which assembled normally at the nuclear rim. Treatment with proteasomal inhibitors led to restoration of levels of HP1 isoforms and also resulted in stable association of lamin mutants with the nuclear periphery, rim localization of the inner nuclear membrane lamin-binding protein emerin and partial improvement of nuclear morphology. A comparison of the stability of HP1 isoforms indicated that HP1alpha and beta displayed increased turnover and higher basal levels of ubiquitination than HP1gamma. Transcript analysis of components of the ubiquitination pathway showed that a specific F-box protein, FBXW10 was induced several-fold in cells expressing lamin mutants. Importantly, ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels.ConclusionsMislocalized lamins can induce ubiquitin-mediated proteasomal degradation of certain HP1 isoforms by activation of FBXW10, a member of the F-box family of proteins that is involved in E3 ubiquitin ligase activity.

Dataset Information

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

Publications

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

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