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

Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic
lateral sclerosis (ALS), but how it protects neurons is not known. STMN2
is known to turn over rapidly and accumulate at axotomy sites. We
confirmed fast turnover of STMN2 in U2OS cells and iPSC-derived neurons
and showed that degradation occurs mainly by the ubiquitin-proteasome
system. The membrane targeting N-terminal domain of STMN2 promoted fast
turnover, whereas its tubulin binding stathmin-like domain (SLD) promoted
stabilization. Proximity labeling and imaging showed that STMN2 localizes
to trans-Golgi network membranes and that tubulin binding reduces this
localization. Pull-down assays showed that tubulin prefers to bind to
soluble over membrane-bound STMN2. Our data suggest that STMN2
interconverts between a soluble form that is rapidly degraded unless bound
to tubulin and a membrane-bound form that does not bind tubulin. We
propose that STMN2 is sequestered and stabilized by tubulin binding, while
its neuroprotective function depends on an unknown molecular activity of
its membrane-bound form.