Nrf2　plays　a　key　role　in　the　protection　of　the　body　against　environmental　stress　via　inducible　expression　of　detoxification　and　antioxidant　enzymes.　Keapl　functions　as　a　sensor　for　oxidative　and　electrophilic　stresses　and　promotes　Nrf2　degradation　via　its　E3　ligase　activity.　Modulation　of　the　Nrf2-Keap1　pathway　has　been　extensively　explored　as　a　strategy　to　combat　against　drug　toxicity　and　stress-induced　diseases.　Here　we　report　a　new　player　that　modulates　the　Nrf2-Keap1　pathway.　PAQR3,　a　membrane　protein　specifically　localized　in　the　Golgi　apparatus,　negatively　regulates　the　expression　of　an　array　of　Nrf2　target　genes　and　alters　cellular　level　of　reactive　oxygen　species.　PAQR3　tethers　Nrf2　and　Keapl,　but　not　small　MAF　proteins　to　the　Golgi　apparatus.　PAQR3　interacts　with　both　Nrf2　and　Keapl　and　facilitates　the　interaction　of　Nrf2　with　Keapl.　PAQR3　promotes　ubiquitination　and　degradation　of　Nrf2.　Disruption　of　PAQR3　interaction　with　Nrf2　and　Keapl　by　a　synthetic　peptide　reduces　Nrf2　ubiquitination　and　elevates　expression　of　Nrf2　target　genes.　At　the　animal　level,　deletion　of　PAQR3　increases　Nrf2　protein　level　and　the　expression　of　Nrf2　target　genes.　In　conclusion,　our　study　pinpoints　that　PAQR3　functions　as　an　adaptor　protein　to　promote　Nrf2-Keap1　complex　formation,　thereby　modulating　the　Nrf2-Keap2　pathway　and　playing　an　important　role　in　controlling　antioxidant　response　of　the　cell.　(C)　2016　Elsevier　Inc.　All　rights　reserved.