Tubulin regulates stability and localization of STMN2 by binding preferentially to its soluble form

The small, tubulin-binding protein STMN2 is highly expressed in neurons
and is implicated in amyotrophic lateral sclerosis. STMN2 degrades rapidly
and accumulates at axotomy sites, suggesting that fast turnover is crucial
for its neuroprotective function. We show that STMN2 was primarily
degraded by the ubiquitin-proteasome system. Its membrane targeting
N-terminal domain promoted fast turnover, whereas its tubulin binding
domain promoted stabilization. Proximity labeling and imaging showed that
tubulin binding reduced STMN2 targeting to trans-Golgi network membranes.
Pull-down assays showed that tubulin binds preferentially to soluble over
membrane-bound STMN2. Our observations suggest that STMN2 interconverts
between a soluble, tubulin-bound form and a membrane-bound, tubulin-free
form and is rapidly degraded when released from both membranes and
tubulin. We propose that tubulin binding sequesters and stabilizes STMN2,
while its neuroprotective function involves an unknown membrane activity.