Nucleotide-binding leucine-rich repeat receptors (NLRs) are central to plant immunity, yet the mechanisms regulating their homeostasis remain poorly understood. In this study, we identify StRWA2 as a susceptibility factor in potato (Solanum tuberosum) that negatively regulates NLR-mediated resistance to Phytophthora infestans. StRWA2 destabilizes NLR proteins R3a and Rpi-blb2 via the 26S proteasome, suppressing NLR-mediated hypersensitive responses (HR). Mechanistically, StRWA2 recruits the E3 ubiquitin ligase StSNIPER2 (SNC1-INFLUENCING PLANT E3 LIGASE REVERSE 2) and enhances its E3 ligase activity, enabling StSNIPER2-dependent ubiquitination and degradation of NLRs. Furthermore, we confirm the necessity of this partnership, where silencing NbSNIPER2a/b reduced StRWA2-mediated plant susceptibility, while expression of a ligase-dead StSNIPER2 variant (StSNIPER2 H123Y) restored NLR stability and plant resistance. Crucially, we obtained StRWA2-silenced potato plants via the RNA interference (RNAi), which conferred resistance to P. infestans with no observable growth penalties compared to wild-type controls. Together, this study identified a susceptibility factor RWA2 from potato that recruits the E3 ligase SNIPER2 to destabilize NLRs. Our findings reveal a critical NLR regulation mode and propose RWA2 as a promising target for engineering disease resistance in crops.

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