Abstract
Protein phosphatase 5 (PP5) is a conserved serine/threonine phosphatase regulating growth, stress responses, programmed cell death and immunity across eukaryotes. However, the mechanisms underlying its activation remain poorly understood. Here we demonstrate that the disruption of the plant MEKK1-MKK1/2-MPK4 cascade activates LET7, a plant homologue of PP5, triggering nucleotide-binding leucine-rich repeat (NLR) SUMM2-mediated autoimmunity in Arabidopsis. The binding of LET7 to the co-chaperone protein HOP1 disrupts the autoinhibitory interaction between the tetratricopeptide repeat and phosphatase domains of LET7 in releasing its phosphatase activity. Activated LET7 subsequently dephosphorylates CRCK3, a crucial kinase regulating SUMM2 autoimmunity. Furthermore, HOP1 and LET7 stabilize SUMM2 via their tetratricopeptide repeat domains, highlighting the dual role of the HOP1-LET7 module in dephosphorylating CRCK3 and stabilizing SUMM2 in NLR-mediated immunity. Our studies reveal a conserved mechanism of PP5 activation across plants and animals and elucidate a unique dephosphorylation cascade governing NLR activation.