Ataxin-3 protects cells against H2O2-induced oxidative stress by enhancing the interaction between Bcl-XL and Bax

•Ataxin-3 protects cells against H2O2-induced oxidative stress.•Ataxin-3 directly binds to Bcl-XL.•The N-terminus of ataxin-3 interacts with the C-terminus of Bcl-XL.•Ataxin-3 enhances the interaction between Bcl-XL and Bax.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder associated with polyglutamine (polyQ) protein ataxin-3. Ataxin-3 is a multi-functional protein, but the precise mechanisms underlying the cellular functions of ataxin-3 remain to be elucidated. Here we demonstrate that ataxin-3 plays a protective role against cellular oxidative stress induced by H2O2 in a Bcl-XL-dependent manner. Ataxin-3 directly interacts with Bcl-XL. The N-terminus of ataxin-3 and the C-terminus of Bcl-XL are essential for the interaction. Ataxin-3 promotes the interaction between Bcl-XL and Bax, but does not affect the ubiquitination and degradation of Bcl-XL. Our data suggest that ataxin-3 plays an important role in regulating the Bcl-XL–Bax-mediated anti-oxidative response by modulating the interaction between Bcl-XL and Bax.