A cell-protecting protein saves neurons by breaking up a lethal molecular couple, Lee et al. reveal.
Stress can be deadly for a neuron. It triggers the cell to manufacture nitric oxide, which reacts with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and causes this enzyme to latch onto another protein, SIAH1. The GAPDH–SIAH1 tandem then slips into the nucleus and kills the cell by ubiquitylating various targets. But stress can also unleash a countervailing pathway, Lee et al. learned.
The researchers were searching for binding partners for the protein B23/nucleophosmin, whose functions include promoting cell survival. The GAPDH–SIAH1 complex turned out to be one of those partners. The team discovered that B23 can swipe nitric oxide from GAPDH and that nitrosylated B23, which showed enhanced binding to SIAH1, prevented GAPDH and SIAH1 from hooking up.
That interference saved cells. Lee et al. engineered cultured neurons to overproduce a normal version of B23 or a mutant version that can’t bind to SIAH1. When they stressed the cells by adding the neurotransmitter NMDA, the researchers found that neurons that contained normal B23 were more likely to survive than were cells with the mutant version. Mice expressing mutant B23 unable to bind SIAH1 developed larger brain lesions in response to NMDA than did control mice, and the lesions were even smaller in mice that overproduced normal B23. These findings suggest that stress activates a cell-killing pathway but also indirectly spurs a cell-sparing pathway. How a neuron balances the two pathways to determine whether it lives or dies remains unclear.
