NDLI: TLR regulation of SPSB1 controls inducible nitric oxide synthase induction.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Blewitt, Marnie E. Willson, Tracy Low, Andrew Nicholson, Sandra E. Lewis, Rowena S. Kolesnik, Tatiana B. D'Cruz, Akshay A. Kuang, Zhihe Masters, Seth L. Norton, Raymond S.
Description	Country affiliation: Australia Author Affiliation: Lewis RS ( Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.)
Abstract	The mammalian innate immune system has evolved to recognize foreign molecules derived from pathogens via the TLRs. TLR3 and TLR4 can signal via the TIR domain-containing adapter inducing IFN-ß (TRIF), which results in the transcription of a small array of genes, including IFN-ß. Inducible NO synthase (iNOS), which catalyzes the production of NO, is induced by a range of stimuli, including cytokines and microbes. NO is a potent source of reactive nitrogen species that play an important role in killing intracellular pathogens and forms a crucial component of host defense. We have recently identified iNOS as a target of the mammalian SPSB2 protein. The SOCS box is a peptide motif, which, in conjunction with elongins B and C, recruits cullin-5 and Rbx-2 to form an active E3 ubiquitin ligase complex. In this study, we show that SPSB1 is the only SPSB family member to be regulated by the same TLR pathways that induce iNOS expression and characterize the interaction between SPSB1 and iNOS. Through the use of SPSB1 transgenic mouse macrophages and short hairpin RNA knockdown of SPSB1, we show that SPSB1 controls both the induction of iNOS and the subsequent production of NO downstream of TLR3 and TLR4. Further, we demonstrate that regulation of iNOS by SPSB1 is dependent on the proteasome. These results suggest that SPSB1 acts through a negative-feedback loop that, together with SPSB2, controls the extent of iNOS induction and NO production.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	7
Volume Number	187
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2011-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Gene Expression Regulation Immunology Macrophages Metabolism Nitric Oxide Synthase Type Ii Biosynthesis Signal Transduction Suppressor Of Cytokine Signaling Proteins Toll-like Receptors Animals Blotting, Western Dna-binding Proteins Genetics Gene Expression Immunoprecipitation Mice Mice, Transgenic Nitric Oxide Rna, Small Interfering Reverse Transcriptase Polymerase Chain Reaction Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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