Nitric oxide is a powerful antimicrobial agent, but production of this toxic molecule is tightly regulated. In The Journal of Immunology, Lewis et al. identify a negative feedback pathway that limits the production of nitric oxide by inducible nitric oxide synthase (iNOS). Toll-like receptor 3 (TLR3) and TLR4 trigger transient upregulation of the ubiquitin ligase adaptor SPSB1. This TLR-mediated TRIF–dependent induction occurs indirectly, as type I interferons or transforming growth factor-β also upregulate SPSB1 expression, albeit with faster kinetics. SPSB1 interacts with iNOS to target it for E3 ubiquitin ligase action and subsequent proteasomal degradation. Transgenic expression of SPSB1 results in lower abundance of iNOS protein and limits the production of nitric oxide, whereas the use of short hairpin RNA targeting SPSB1 leads to pronounced production of nitric oxide. Thus, the delayed induction of SPSB1 by TLRs allows cells to transiently produce nitric oxide via iNOS that is induced by the same stimulus.
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Dempsey, L. NO regulation. Nat Immunol 12, 931 (2011). https://doi.org/10.1038/ni.2130
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DOI: https://doi.org/10.1038/ni.2130
