SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated innate immunity and lifespan extension

Animals respond to mitochondrial stress with the induction of mitochondrial unfolded protein response (UPR(mt)). A cascade of events occur upon UPR(mt) activation, ultimately triggering a transcriptional response governed by two transcription factors: DVE-1 and ATFS-1. Here we identify SUMO-specific peptidase ULP-4 as a positive regulator of C. elegans UPR(mt) to control SUMOylation status of DVE-1 and ATFS-1. SUMOylation affects these two axes in the transcriptional program of UPR(mt) with distinct mechanisms: change of DVE-1 subcellular localization vs. change of ATFS-1 stability and activity. Our findings reveal a post-translational modification that promotes immune response and lifespan extension during mitochondrial stress.