The homeostasis of resistance (R) proteins in plants must be tightly regulated to ensure precise activation of plant immune response upon pathogen infection, while avoiding autoimmunity and growth defects when plants are uninfected. The ubiquitin-proteasome system (UPS) is a universal mechanism of protein homeostasis control in eukaryotes, and it was shown to be one of the mechanisms that regulate R protein levels. In particular, E3 ubiquitin ligase directly interacts with substrate proteins and largely determines the substrate specificity targeted for ubiquitination and proteasomal degradation. It was known that CPR1, an F-box protein in the SCF E3 complex, functions as a negative regulator of plant immunity through targeting R proteins SNC1 and RPS2 for degradation. However, whether or not those R proteins are targeted by other E3 ligases is unclear. In this paper, MUSE16, which encodes a RING-type E3 ligase, was isolated from a forward genetic screen and suggested to be a negative regulator of plant immunity. Unlike CPR1, knocking out MUSE16 in Arabidopsis thaliana alone is not enough to result in defense related dwarfism, since only RPS2 out of the tested R proteins accumulated in muse16. Thus, our study identified another E3 ligase involved in NLR R protein degradation, supporting that Ub-mediated degradation is a fine-tuned mechanism for regulating the turnover of R proteins in plants, and the same R protein can be targeted by different E3 ligases for its homeostasis regulation.