RAPID DEGRADATION OF NEWLY SYNTHESIZED TUBULIN IN LITHIUM-TREATED SENSORY NEURONS

When cultured chick sensory neurons were labeled with [S-35]methionine for 1 h or longer in the presence of 5-25 mM LiCl, we found a dose-dependent reduction in the level of radiolabeled tubulin, to one third of control levels, with no noticeable effect on other proteins. The magnitude of this response was identical after a 1-h or 72-h preincubation in 25 mM LiCl and returned to control values within 1 h after removal of LiCl. Short (5-min) pulse-chase experiments revealed that tubulin synthesis was not affected by Li+, but that newly synthesized tubulin was rapidly degraded, such that 50% of the labeled beta-tubulin was lost within 5 min. There was no enhanced degradation of tubulin present before exposure to Li+. Addition of LiCl at various times before and after a 10-min pulse suggested that tubulin becomes completely refractory to Li+-induced degradation within 10 min after translation. Although Li+ treatment resulted in a decrease in the fraction of extant tubulin present in the unassembled form, the Li+-induced degradation of nascent tubulin is not a consequence of shifts in assembly state, because colcemid or taxol treatment did not lead to rapid degradation of newly synthesized tubulin, and neither drug altered the response to Li+. We suggest that Li+ interferes with the correct folding of tubulin polypeptides, exposing sites, normally hidden, to the action of a protease(s).