The protein RAB5IF promotes BDNF signaling by stimulating the SUMOylation of Gα _i1/3 to reduce depressive-like behaviors in mice

Chronic stress and impaired signaling by the neurotrophic factor BDNF are associated with depression. The heterotrimeric G protein subunits Gα_i1 and Gα_i3 (Gα_i1/3) are critical mediators of BDNF signaling in a mouse model of chronic mild stress-induced depression. Here, we found that chronic mild stress impairs the SUMOylation of Gα_i1/3 and, consequently, their formation of signaling complexes with the BDNF receptor TrkB. Impaired SUMOylation of the G protein subunits was the result of a decrease in RAB5-interacting factor (RAB5IF) and a consequent decrease in the translational efficiency of <i>Sumo2</i> mRNA. RAB5IF silencing or knockout in cultured murine hippocampal neurons impaired BDNF-induced signaling and mitochondrial function that compromised dendritic branching and synaptic density. Neuronal knockdown or conditional knockout of RAB5IF in the mouse hippocampus recapitulated these cellular deficits and induced depressive-like behaviors. Conversely, neuronal overexpression of RAB5IF in the hippocampus mitigated the depressive phenotype. SUMOylation of Gα_i1/3 at Lys²⁷⁷ was required for BDNF-induced formation of TrkB-SUMO2-Gα_i1/3 complexes and activation of downstream Akt-mTOR signaling. Neuronal knockdown of SUMO2 or hippocampal overexpression of a Gα_i1/3 mutant that could not be SUMOylated impaired BDNF signaling and induced depressive-like behaviors in mice. The findings reveal that the RAB5IF-SUMO2-Gα_i1/3 signaling axis is crucial for TrkB signaling and preventing depressive behaviors.