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Multiple redox regulation in NF-kappaB transcription factor activation
1Laboratory of Virology, Institute of Pathology, University of Liège, Belgium.
Abstract:
The well-known Rel/NF-kappaB family of vertebrate transcription factors comprises a number of structurally related, interacting proteins that bind DNA as dimers and whose activity is regulated by subcellular location. This family includes many members (p50, p52, RelA, RelB, c-Rel, ...), most of which can form DNA-binding homo- or hetero-dimers. All Rel proteins contain a highly conserved domain of approximately 300 amino-acids, called the Rel homology domain (RH), which contains sequences necessary for the formation of dimers, nuclear localization, DNA binding and IkappaB binding. Nuclear expression and consequent biological action of the eukaryotic NF-kappaB transcription factor complex are tightly regulated through its cytoplasmic retention by ankyrin-rich inhibitory proteins known as IkappaB. The IkappaB proteins include a group of related proteins that interact with Rel dimers and regulate their activities. The interaction of a given IkappaB protein with a Rel complex can affect the Rel complex in distinct ways. In the best characterized example, IkappaB-alpha interacts with a p50/RelA (NF-kappaB) heterodimer to retain the complex in the cytoplasm and inhibit its DNA-binding activity. The NF-kappaB/IkappaB-alpha complex is located in the cytoplasm of most resting cells, but can be rapidly induced to enter the cell nucleus. Upon receiving a variety of signals, many of which are probably mediated by the generation of reactive oxygen species (ROS), IkappaB-alpha undergoes phosphorylation at serine residues by a ubiquitin-dependent protein kinase, is then ubiquitinated at nearby lysine residues and finally degraded by the proteasome, probably while still complexed with NF-kappaB. Removal of IkappaB-alpha uncovers the nuclear localization signals on subunits of NF-kappaB, allowing the complex to enter the nucleus, bind to DNA and affect gene expression. Like proinflammatory cytokines (e.g. IL-1, TNF), various ROS (peroxides, singlet oxygen, ...) as well as UV (C to A) light are capable of mediating NF-kappaB nuclear translocation, while the sensor molecules which are sensitive to these agents and trigger IkappaB-alpha proteolysis are still unidentified. We also show that a ROS-independent mechanism is activated by IL-1beta in epithelial cells and seems to involve the acidic sphingomyelinase/ceramide transduction pathway.
Insights
The NF-kappaB (nuclear factor kappa B) transcription factor complex is regulated by IkappaB proteins. Signals trigger IkappaB degradation, allowing NF-kappaB to enter the nucleus and activate gene expression.
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- The Rel/NF-kappaB family of transcription factors are key regulators of gene expression.
- These factors form dimers and their activity is controlled by their location within the cell.
- Cytoplasmic retention by inhibitory proteins called IkappaB regulates NF-kappaB activity.
Purpose of the Study:
- To elucidate the regulatory mechanisms of NF-kappaB (nuclear factor kappa B) transcription factor activity.
- To understand how IkappaB proteins control NF-kappaB localization and function.
- To identify signaling pathways that lead to NF-kappaB activation.
Main Methods:
- The study focuses on the interaction between Rel proteins and IkappaB proteins.
- It describes the process of IkappaB-alpha degradation via phosphorylation, ubiquitination, and proteasomal pathways.
- It investigates signaling molecules like reactive oxygen species (ROS) and interleukins (IL-1, TNF) that induce NF-kappaB nuclear translocation.
Main Results:
- IkappaB-alpha binds to NF-kappaB dimers, retaining them in the cytoplasm.
- Degradation of IkappaB-alpha unmasks nuclear localization signals, enabling NF-kappaB entry into the nucleus.
- Reactive oxygen species (ROS), inflammatory cytokines, and UV light can trigger NF-kappaB nuclear translocation.
- A ROS-independent pathway involving acidic sphingomyelinase/ceramide is activated by IL-1beta in epithelial cells.
Conclusions:
- NF-kappaB activation is a tightly regulated process involving cytoplasmic sequestration and subsequent degradation of IkappaB inhibitors.
- Multiple signaling pathways, including ROS-dependent and -independent mechanisms, converge to control NF-kappaB nuclear translocation.
- Understanding these pathways is crucial for comprehending immune responses and inflammatory processes.