- Cysteine synthases or O-Acetylserine (thiol) lyases (OASTLs) are evolutionary conserved proteins among many prokaryotes and eukaryotes that carry out sulfur acquisition and synthesis of cysteine. A mutation in the cytosolic OASTL-A1/ONSET OF LEAF DEATH3 (OLD3) was previously shown to reduce the OASTL activity of the old3-1 protein in vitro and cause autonecrosis in specific Arabidopsis accessions. Here we investigated why a mutation in this protein causes autonecrosis in some but not other accessions. The autonecrosis was found to depend on Recognition of Peronospora Parasitica 1 (RPP1)-like disease resistance R gene(s), from an evolutionary divergent R gene cluster present in Ler-0 but not the reference accession Col-0. RPP1-like gene(s) show a negative epistatic interaction to the old3-1 mutation which is not linked with reduced cysteine biosynthesis. Metabolic profiling and transcriptional analysis further indicates that an effector triggered-like immune response and metabolic disorder is associated with autonecrosis in old3-1 mutants, likely activated by an RPP1-like gene. However, old3-1 itself renders largely neutral changes in primary plant metabolism, stress-defence and immune responses. Finally we showed that lack of functional OASTL-A1 results in enhanced disease susceptibility against infection with virulent and non-virulent Pseudomonas syringae pv. tomato DC3000 strains. These results reveal an interaction between the cytosolic OASTL and components of plant immunity. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.