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The SOCS box protein SPSB2 targets inducible nitric oxide synthase (iNOS) for degradation to prevent the enzyme from damaging tissues following pathogen infection, Kuang et al. say.
SOCS box proteins recruit E3 ubiquitin ligases to modify specific proteins and target them for destruction by the proteasome. SPSB2 is part of a subfamily of SOCS box proteins whose physiological substrates are largely unknown. Kuang et al. found that one of SPSB2's targets is iNOS, the enzyme that generates nitric oxide (NO) and other reactive nitrogen species to fight invading pathogens such as Leishmania major.
NO is cytotoxic, so iNOS must be removed once an infection has been resolved. SPSB2 bound to iNOS and induced its ubiquitination. The enzyme was rapidly turned over by macrophages overexpressing SPSB2, whereas macrophages lacking SPSB2 degraded iNOS slowly. But the lack of SPSB2 has an upside: iNOS and NO levels were higher in SPSB2-deficient macrophages, allowing the cells to kill invading Leishmania with greater efficiency.
SPSB2 expression is suppressed by the same stimuli that induce iNOS production, so the SOCS box protein only down-regulates iNOS once an infection has passed. But authors Sandra Nicholson and Ray Norton think that inhibiting the SPSB2–iNOS interaction could help treat chronic diseases like tuberculosis, prolonging iNOS's lifetime to kill off persistent, low-level infections. They also want to investigate whether other members of the SPSB family target iNOS for degradation as well.