A key outcome of glucocorticoid (GC) treatment in patients with inflammatory and autoimmune diseases is upregulation of the glucocorticoid-induced leucine zipper (GILZ). GILZ acts as a natural brake against activation, expansion and effector responses of B cells, CD4 T cells, macrophages and dendritic cells, and collectively these effects confer protection from damage in autoimmune diseases. GILZ is downregulated in inflammatory contexts and restoration of GILZ is an attractive therapeutic avenue. Developing a strategy to achieve this requires an understanding of the mechanisms governing GILZ abundance. Here, we show K48 and K63 linked polyubiquitination and proteasomal degradation of GILZ, which we found to have a half-life approximately 45-60 minutes. Importantly, the stability of the GILZ protein was not altered by GC treatment or by stimulation of cells with inflammatory signals, including agonists of toll-like receptors (TLRs) 4, 7 and 9, although these ligands rapidly stifled GILZ transcription. This demonstrates that GILZ abundance is regulated through gene transcription rather than protein turnover, which remains stable. We identified a non-redundant E3 ligase of GILZ, deletion of which more than doubled GILZ half-life. This discovery provides guidance towards a potential mechanism for manipulating GILZ abundance and its associated consequences across the immune system.