KPNA6 (Importin α7)-Mediated Nuclear Import of Keap1 Represses the Nrf2-Dependent Antioxidant Response
- 1 May 2011
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 31 (9), 1800-1811
- https://doi.org/10.1128/mcb.05036-11
Abstract
The transcription factor Nrf2 has emerged as a master regulator of cellular redox homeostasis. As an adaptive response to oxidative stress, Nrf2 activates the transcription of a battery of genes encoding antioxidants, detoxification enzymes, and xenobiotic transporters by binding the cis-antioxidant response element in the promoter regions of genes. The magnitude and duration of inducible Nrf2 signaling is delicately controlled at multiple levels by Keap1, which targets Nrf2 for redox-sensitive ubiquitin-mediated degradation in the cytoplasm and exports Nrf2 from the nucleus. However, it is not clear how Keap1 gains access to the nucleus. In this study, we show that Keap1 is constantly shuttling between the nucleus and the cytoplasm under physiological conditions. The nuclear import of Keap1 requires its C-terminal Kelch domain and is independent of Nrf1 and Nrf2. We have determined that importin α7, also known as karyopherin α6 (KPNA6), directly interacts with the Kelch domain of Keap1. Overexpression of KPNA6 facilitates Keap1 nuclear import and attenuates Nrf2 signaling, whereas knockdown of KPNA6 slows down Keap1 nuclear import and enhances the Nrf2-mediated adaptive response induced by oxidative stress. Furthermore, KPNA6 accelerates the clearance of Nrf2 protein from the nucleus during the postinduction phase, therefore promoting restoration of the Nrf2 protein to basal levels. These findings demonstrate that KPNA6-mediated Keap1 nuclear import plays an essential role in modulating the Nrf2-dependent antioxidant response and maintaining cellular redox homeostasis.Keywords
This publication has 52 references indexed in Scilit:
- The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1Nature, 2010
- Prothymosin-α Mediates Nuclear Import of the INrf2/Cul3·Rbx1 Complex to Degrade Nuclear Nrf2Online Journal of Public Health Informatics, 2009
- Six Classes of Nuclear Localization Signals Specific to Different Binding Grooves of Importin αJournal of Biological Chemistry, 2009
- Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress ResponseMolecular and Cellular Biology, 2007
- Keap1 Controls Postinduction Repression of the Nrf2-Mediated Antioxidant Response by Escorting Nuclear Export of Nrf2Molecular and Cellular Biology, 2007
- Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulumBiochemical Journal, 2006
- Ubiquitination of Keap1, a BTB-Kelch Substrate Adaptor Protein for Cul3, Targets Keap1 for Degradation by a Proteasome-independent PathwayOnline Journal of Public Health Informatics, 2005
- Keap1 Regulates the Oxidation-Sensitive Shuttling of Nrf2 into and out of the Nucleus via a Crm1-Dependent Nuclear Export MechanismMolecular and Cellular Biology, 2005
- Crystal Structure of the Kelch Domain of Human Keap1Online Journal of Public Health Informatics, 2004
- Up-Regulation of the Human γ-Glutamylcysteine Synthetase Regulatory Subunit Gene Involves Binding of Nrf-2 to an Electrophile Responsive ElementBiochemical and Biophysical Research Communications, 1999