Abstract
The nuclear factor κB (NF-κB) signaling pathway ubiquitously controls cell growth and survival in basic conditions as well as rapid resetting of cellular functions following environment changes or pathogenic insults. Moreover, its deregulation is frequently observed during cell transformation, chronic inflammation or autoimmunity. Understanding how it is properly regulated therefore is a prerequisite to managing these adverse situations. Over the last years evidence has accumulated showing that ubiquitination is a key process in NF-κB activation and its resolution. Here, we examine the various functions of ubiquitin in NF-κB signaling and more specifically, how it controls signal transduction at the molecular level and impacts in vivo on NF-κB regulated cellular processes.
Highlights
Regulation of gene expression in eukaryotic cells represents an essential process for the timely control of the production of proteins, while the fine-tuning of their final activities and/or fate often relies upon post-translational modifications (PTM)
Linear ubiquitin chain assembly complex (LUBAC) is the only E3 ligase complex described so far that is able to synthesize M1-linked ubiquitin chains in mammalian cells [28,29]. It is composed of three subunits, haem-oxydized IRP2 ubiquitin Ligase 1L (HOIL-1L), HOIL-interacting protein (HOIP)
Jin et al [250] demonstrated a non-redundant function of cIAPs and X-linked inhibitor of apoptosis protein (XIAP) in the genotoxic stress pathway and proposed that cellular inhibitor of apoptosis protein-1 (c-IAP1) may be the E3 ligase responsible for NEMO monoubiquitination
Summary
Regulation of gene expression in eukaryotic cells represents an essential process for the timely control of the production of proteins, while the fine-tuning of their final activities and/or fate often relies upon post-translational modifications (PTM). Among the many cellular processes that are regulated by ubiquitination is signal transduction which needs to be tightly controlled for operating properly at the right place and time. One of the first identified and most extensively dissected signaling pathways regulated by ubiquitination is the NF-κB pathway that plays a critical role in inflammation, immunity and control of cell death and proliferation. Not surprisingly, this pathway represents a useful paradigm to illustrate how ubiquitination controls protein activity. We will describe how perturbations in ubiquitination and ubiquitin recognition mechanisms in the NF-κB pathway impact on human health
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