Physical and Functional Interaction of Sequestosome 1 with Keap1 Regulates the Keap1-Nrf2 Cell Defense Pathway

• DOI: 10.1074/jbc.m109.096545
• Publication Date: 2010-04-09T00:18:10Z
• Authors: Ian M. Copple; Adam Lister; Akua D. Obeng; Neil R. Kitteringham; Rosalind E. Jenkins; Robert Layfield; Brian J. Foster; Christopher E. Go...; B. Kevin Park
• Keywords: Sequestosome 1; KEAP1

Nrf2 regulates the expression of numerous cytoprotective genes in mammalian cells. The activity is regulated by Cul3 adaptor Keap1, yet little known regarding mechanisms regulation Keap1 itself. Here, we have used immunopurification and mass spectrometry, addition to immunoblotting, identify sequestosome 1 (SQSTM1) as a cellular binding partner Keap1. SQSTM1 serves scaffold various signaling pathways shuttles polyubiquitinated proteins proteasomal lysosomal degradation machineries. Ectopic led decrease basal protein level panel Furthermore, RNA interference (RNAi) depletion resulted an increase concomitant absence changes or mRNA levels. increased cells depleted RNAi was linked its rate degradation; half-life almost doubled SQSTM1. decreased associated with decreases levels, function several Nrf2-regulated cell defense genes. dispensable for induction Keap1-Nrf2 pathway, activation tert-butylhydroquinone iodoacetamide not affected These findings demonstrate physical functional interaction between reveal additional layer pathway.