Proteasomal degradation of GRα via the ubiquitin–proteasomal system (UPS). Ubiquitination of the GRα requires multiple rounds of enzymatic processing before proteasomal degradation occurs. An activating enzyme, E1, activates ubiquitin and transfers it to a conjugating enzyme, E2. Hereafter, an E3 ligase from the RING finger family binds the GRα and recruits it to E2, which transfers the activated ubiquitin to K419 of the human GRα or K426 of the mouse GRα, until a poly-ubiquitin chain is formed. Once the poly-ubiquitin chain is complete, GRα is delivered to the proteasome and degraded, resulting in the release of GRα protein fragments and the poly-ubiquitin chain.