Ubiquitin regulatory X (UBX) domain–containing proteins are cofactors of the Cell Division Cycle 48 (CDC48) and play vital roles in protein quality control 1,2. Although compelling evidence suggests that CDC48s are essential regulators of plant immunity 3, little is known about whether and how the cofactors of CDC48, such as plant UBX-containing (PUX) proteins, participate in immune responses. We discovered that MoNLE1, an effector from the fungal pathogen Magnaporthe oryzae that localizes to the host nucleus, is a core virulence factor that suppresses rice immunity by specifically interfering with OsPUX8B.2. The UBX domain of OsPUX8B.2 is required for its binding to OsATG8 and OsCDC48-6 and controls its 26S proteasome–dependent stability. OsPUX8B.2 and OsCDC48-6 positively regulate plant immunity against blast fungus, while high-temperature tolerance heat shock protein OsBHT, a putative cytoplasmic substrate of OsPUX8B.2–OsCDC48-6, negatively regulates defense against blast infection. MoNLE1 promotes the nuclear migration and degradation of OsPUX8B.2 and disturbs its association with OsBHT. Given the high conservation of MoNLE1, plants with broad and durable blast resistance might be generated by engineering intracellular proteins resistant to MoNLE1.