Trends in Immunology
ReviewNew insights into NF-κB regulation and function
Introduction
NF-κB (nuclear factor-κB) regulates genes involved at multiple stages of immune responses, including innate immune cell activation, inflammation, dendritic cell maturation and lymphocyte activation. NF-κB activation is tightly controlled by canonical and atypical pathways that regulate proteolysis of IκB (an inhibitor of NF-κB) and IκB-related proteins (Box 1; Figure 1). Because such basic knowledge of NF-κB has been discussed previously 1, 2, this review will instead focus on new insights gained through recent studies.
Section snippets
Regulation of canonical NF-κB signaling by ubiquitination and deubiquitination
Protein ubiquitination plays a critical role in NF-κB activation. Initially shown to mediate proteasomal degradation of IκBs and processing of NF-κB precursors, ubiquitination is now known to also serve as a nondegradative mechanism for activation of the canonical NF-κB pathway (Box 2). This latter function involves the addition of lysine 63 (K63)-linked ubiquitin chains to specific target proteins.
Noncanonical pathway of NF-κB activation
Processing of p100 and inducible degradation of p105 represent two major atypical pathways of NF-κB activation, with the former being known as the noncanonical NF-κB pathway (Figure 1a). Because p100 and p105 function as both NF-κB precursor proteins and IκB-like molecules (Box 1), their processing and degradation play important roles in mediating NF-κB signaling. The regulation of p105-specific pathway has been thoroughly discussed in a previous review [1], and this section focuses on the
RelA phosphorylation
Posttranslational modification of Rel subunits and their association with other nuclear proteins are critical to regulate the transcriptional activity and specificity of NF-κB dimers (see Refs. 2, 48 for recent reviews). For example, RelA phosphorylation on S276 promotes its interaction with the histone acetyltransferases CBP (CREB-binding protein) and p300 while displacing repressive histone deacetylase (HDAC) proteins [49] (Figure 3). The physiological significance of RelA S276
Concluding remarks
It has now been > 20 years since the original identification of NF-κB as a regulator of κB light chain expression in B cells. Nevertheless, NF-κB is still a major area of research and serves as a paradigm for a signaling pathway that is regulated by ubiquitination. The importance of NF-κB in inflammation, autoimmunity and cancer is clearly established, and there has been a considerable effort by the pharmaceutical industry to develop IKK inhibitors to treat these diseases. However, such
Acknowledgements
Work performed in the authors’ laboratory is supported by the University of Texas MD Anderson Cancer Center, and National Institutes of Health Grants R01 AI064639, R01 AI057555, and R01 CA94922 (to S.C.S.) and UK Medical Research Council (to S.C.L.). We apologize to those investigators whose work was not cited because of space limitations.
Glossary
- ABIN
- A20-binding inhibitor of NF-κB
- BAFFR
- B cell–activating factor receptor
- CBP
- CREB-binding protein
- CDK
- cyclin-dependent kinase
- ChIp
- chromatin immunoprecipitation
- c-IAP
- cellular inhibitor of apoptosis
- CYLD
- cylindromatosis
- DUB
- deubiquitinating enzyme
- ECSSOCS1
- ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1
- HDAC
- histone deacetylase
- IKK
- IκB kinase
- IκB
- inhibitor of NF-κB
- LTßR
- lymphotoxin β receptor
- MAP3K
- MAP kinase kinase kinase
- NF-κB
- nuclear factor-κB
- NIK
- NF-κB–inducing kinase
- RANK
- receptor activator of NF-κB
- RIP1
References (76)
- et al.
Shared principles in NF-κB signaling
Cell
(2008) A genomic and functional inventory of deubiquitinating enzymes
Cell
(2005)CYLD inhibits tumor cell proliferation by blocking bcl-3-dependent NF-κB signaling
Cell
(2006)A20 and A20-binding proteins as cellular inhibitors of nuclear factor-κB-dependent gene expression and apoptosis
Biochem. Pharmacol.
(2000)The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals
Immunity
(2008)ABIN-1 binds to NEMO/IKKγ and co-operates with A20 in inhibiting NF-κB
J. Biol. Chem.
(2006)Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD
Dev. Cell
(2007)Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells
J. Biol. Chem.
(2007)Optineurin negatively regulates TNFα-induced NF-κB activation by competing with NEMO for ubiquitinated RIP
Curr. Biol.
(2007)Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins
J. Biol. Chem.
(2008)
NF-κB-inducing kinase regulates the processing of NF-κB2 p100
Mol. Cell
βTrCP binding and processing of NF-κB2/p100 involve its phosphorylation at serines 866 and 870
Cell. Signal.
Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation
J. Biol. Chem.
IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis
Cell
IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis
Cell
Smac mimetics and TNFα: a dangerous liaison?
Cell
TRAF2 differentially regulates the canonical and noncanonical pathways of NF-κB activation in mature B cells
Immunity
TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor
Immunity
Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation
Trends Biochem. Sci.
Phosphorylation of CBP by IKKα promotes cell growth by switching the binding preference of CBP from p53 to NF-κB
Mol. Cell
Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA
Mol. Cell
COMMD proteins: a novel family of structural and functional homologs of MURR1
J. Biol. Chem.
Proinflammatory stimuli induce IKKα-mediated phosphorylation of PIAS1 to restrict inflammation and immunity
Cell
Ribosomal protein S3: a KH domain subunit in NF-κB complexes that mediates selective gene regulation
Cell
Genome-wide mapping of RELA(p65) binding identifies E2F1 as a transcriptional activator recruited by NF-κB upon TLR4 activation
Mol. Cell
Functions of NF-κB1 and NF-κB2 in immune cell biology
Biochem. J.
Ubiquitin signaling in the NF-κB pathway
Nat. Cell Biol.
Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling
Nat. Immunol.
K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo
J. Immunol.
Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses
Proc. Natl. Acad. Sci. U. S. A.
Cutting Edge: Pivotal function of Ubc13 in thymocyte TCR signaling
J. Immunol.
Malt1 ubiquitination triggers NF-kB signaling upon T-cell activation
EMBO J.
The CARMA1 signalosome links the signaling machinery of adaptive and innate immunity in lymphocytes
Nat. Rev. Immunol.
NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-κB activation
Proc. Natl. Acad. Sci. U. S. A.
Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways
EMBO J.
The Yersinia enterocolitica effector YopP inhibits host cell signaling by inactivating the protein kinase TAK1 in the IL-1 signaling pathway
EMBO Rep.
Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses
J. Exp. Med.
Deubiquitylation and regulation of the immune response
Nat. Rev. Immunol.
Cited by (250)
Crosstalk between inflammasomes, inflammation, and Nrf2: Implications for gestational diabetes mellitus pathogenesis and therapeutics
2024, European Journal of PharmacologyMolecular characterization and functional analysis of a mollusk Rel homologous gene
2023, Fish and Shellfish ImmunologyInvestigating regulated signaling pathways in therapeutic targeting of non-small cell lung carcinoma
2023, Biomedicine and Pharmacotherapy