Mitogen-activated protein kinase (MAPK) cascades are highly conserved signaling modules that regulate plant immune responses. The Arabidopsis thaliana Raf-like MAPK kinase kinase ENHANCED DISEASE RESISTANCE1 (EDR1) is a key negative regulator of plant immunity that affects the protein levels of MKK4 and MKK5, two important MAPK cascade members, but the underlying mechanism is poorly understood. Here, genome-wide phosphorylation analysis demonstrated that the E3 ligase KEEP ON GOING (KEG) is phosphorylated in the edr1 mutant but not the wild type, suggesting that EDR1 neg-atively affects KEG phosphorylation. The identified phosphorylation sites in KEG appear to be important for its accumulation. The keg-4 mutant, a previously identified edr1 suppressor, enhances susceptibility to the powdery mildew pathogen Golovinomyces cichoracearum. In addition, MKK4 and MKK5 protein levels are reduced in the keg-4 mutant. Furthermore, we demonstrate that MKK4 and MKK5 associate with full-length KEG, but not with truncated KEG-RK or KEG-RKA, and that KEG ubiquitinates and medi-ates the degradation of MKK4 and MKK5. Taken together, these results indicate that MKK4 and MKK5 protein levels are regulated by KEG via ubiquitina-tion, uncovering a mechanism by which plants fine-tune immune responses by regulating the homeo-stasis of key MAPK cascade members via ubiquiti-nation and degradation.