title: Aberrant sumoylation signaling evoked by reactive oxygen species impairs protective function of Prdx6 by destabilization and repression of its transcription.
abstract: Loss of the cytoprotective protein peroxiredoxin 6 (Prdx6) in cells that are aging or under oxidative stress is known to be linked to the pathobiology of many age-related diseases. However, the mechanism by which Prdx6 activity goes awry is largely unknown. Using Prdx6-deficient (Prdx6(-/-) ) cells as a model for aging or redox active cells, human/mouse lens epithelial cells (LECs) facing oxidative stress and aging lenses, we found a significant increase in the levels of small ubiquitin-like modifier (Sumo)1 conjugates. These cells displayed increased levels of Sumo1 and reduced the expression of Prdx6. Specifically, we observed that Prdx6 is a target for aberrant sumoylation signaling, and that Sumo1 modification reduces its cellular abundance. LECs overexpressing Sumo1 showed reduced expression and activity of Prdx6 and its transactivator specificity protein 1 (Sp1), mRNA and protein with increased levels of reactive oxygen species; those cells were vulnerable to oxidative stress-induced cell death. A significant reduction in Prdx6, Sp1 protein and mRNA expression was observed in redox active Prdx6(-/-) cells and in aging lenses/LECs. The reduction was correlated with increased expression of Sumo1 and enrichment of the inactive form (dimeric) of Sumo-specific protease (Senp)1. Experiments with Sumo1-fused Prdx6 and Prdx6 promoter-linked to chloramphenicol acetyltransferase reporter gene constructs indicated that Sumo1 dysregulated Prdx6 activity by reducing its abundance and attenuating its transcription; in contrast, the delivery of Senp1 or Prdx6 reversed the process. The data show that reactive oxygen species-evoked aberrant sumoylation signaling affects Prdx6 activity by reducing Prdx6 abundance, as well as transcription. The findings of the present study may provide a foundation for a strategy to repair deleterious oxidative signaling generated by a reduced activity of Prdx6.
authors.affiliation: Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Chhunchha
authors.forename: Nigar
authors.initials: N
authors.lastname: Fatma
authors.forename: Eri
authors.initials: E
authors.lastname: Kubo
authors.forename: Dhirendra P
authors.initials: DP
authors.lastname: Singh
mesh_terms: D000375:Aging; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D004794:Enzyme Repression; D004795:Enzyme Stability; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D054465:Peroxiredoxin VI / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D014158:Transcription, Genetic
chemical_list: D017382:Reactive Oxygen Species; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D016329:Sp1 Transcription Factor; C515977:PRDX6 protein, human; D054465:Peroxiredoxin VI; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases
keywords: Prdx6; Senp1; Sumo1; cell survival; oxidative stress