We previously demonstrated that CRAM (CRMP5)-associated
GTPase (CRAG), a short splicing variant of centaurin-γ3/AGAP3, facilitated degradation of expanded
polyglutamine protein (
polyQ) via the nuclear
ubiquitin-
proteasome pathway. Taking advantage of this feature, we also showed that lentivirus-mediated CRAG expression in the Purkinje cells of mice expressing
polyQ resulted in clearance of the
polyQ aggregates and rescue from
ataxia. However, the molecular basis of the function of CRAG in cell survival against
polyQ remains unclear. Here we report that CRAG, but not centaurin-γ3, induces transcriptional activation of c-Fos-dependent
activator protein-1 (AP-1) via
serum response factor (SRF). Mutation analysis indicated that the
nuclear localization signal and both the N- and C-terminal regions of CRAG are critical for SRF-dependent c-Fos activation. CRAG knockdown by
siRNA or expression of a dominant negative mutant of CRAG significantly attenuated the c-Fos activation triggered by either
polyQ or the
proteasome inhibitor MG132. Importantly, c-Fos expression partially rescued the enhanced cytotoxicity of CRAG knockdown in
polyQ-expressing or MG132-treated cells. Finally, we suggest the possible involvement of CRAG in the sulfiredoxin-mediated
antioxidant pathway via
AP-1. Taken together, these results demonstrated that CRAG enhances the cell survival signal against the accumulation of unfolded
proteins, including
polyQ, through not only
proteasome activation, but also the activation of c-Fos-dependent
AP-1.