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IκB kinase complexes: gateways to NF-κB activation and transcription

Abstract

Transcription factors of the NF-κB family regulate hundreds of genes in the context of multiple important physiological and pathological processes. NF-κB activation depends on phosphorylation-induced proteolysis of inhibitory IκB molecules and NF-κB precursors by the ubiquitin-proteasome system. Most of the diverse signaling pathways that activate NF-κB converge on IκB kinases (IKK), which are essential for signal transmission. Many important details of the composition, regulation and biological function of IKK have been revealed in the last years. This review summarizes current aspects of structure and function of the regular stoichiometric components, the regulatory transient protein interactions of IKK and the mechanisms that contribute to its activation, deactivation and homeostasis. Both phosphorylation and ubiquitinatin (destructive as well as non-destructive) are crucial post-translational events in these processes. In addition to controlling induced IκB degradation in the cytoplasm and processing of the NF-κB precursor p100, nuclear IKK components have been found to act directly at the chromatin level of induced genes and to mediate responses to DNA damage. Finally, IKK is engaged in cross talk with other pathways and confers functions independently of NF-κB.

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Abbreviations

Act1:

NF-κB activator 1

ATM:

Ataxia telangiectasia mutated

βTrCP:

β transducin repeat-containing protein

BAFF:

B cell-activating factor

Bcl-3:

B cell lymphoma 3

Bcl-10:

B cell lymphoma 10

BCMA:

B cell maturation antigen

CARMA:

Caspase-recruitment-domain-containing membrane-associated guanylate kinase

Cardif:

CARD adaptor inducing IFN-β

CBP:

CREB binding protein

Cdc37:

Cell division cycle 37

cIAP:

Inhibitor of apoptosis protein

CIKS:

connection to IKK and SAPK/JNK

CSN3:

COP9 signalosome component 3

CYLD:

cylindromatosis protein

Dok1:

docking protein 1

EHV:

Equine herpesvirus

ELKS:

Protein rich in amino acids E, L, K and S

ENaC:

Epithelial Na+ channel

ERα:

estrogen receptor α

ERK:

extracellular signal-regulated kinase

FANCA:

Fanconi anemia complementation group A

FGF8:

Fibroblast growth factor 8

FKBP51:

FK506-binding protein 51 kDa

FOXO3a:

Forkhead box transcription factor

GITR:

Glucocorticoid-induced TNF receptor

HCV:

Hepatitis C virus

HDAC:

Histone deacetylase

HIF-2α:

Hypoxia-induced factor 2α

HPK1:

Hematopoietic progenitor kinase 1

Hsp:

Heat shock protein

hTid1:

Human tumorous imaginal disc 1 protein

HTLV-1:

Human T-cell leukemia virus-1

Htt:

Huntingtin protein

HVEM:

Herpes virus entry mediator

IκB:

Inhibitor of kappaB binding

IKK:

IκB kinase

IL-1:

Interleukin-1

IRAK1:

Interleukin-1 receptor-associated kinase 1

IRF-7:

Interferon regulatory factor-7

IRS-1:

Insulin receptor substrate-1

JNK:

c-Jun N-terminal kinase

KSHV:

Kaposi's-sarcoma-associated herpesvirus

LMP1:

Latent membrane protein

LPS:

Lipopolysaccharide

LTβ:

Lymphotoxin β

LTβR:

Lymphotoxin β receptor

MALT:

Mucosa-associated lymphoid tissue lymphoma translocation protein 1

MEKK:

Mitogen-activated protein/ERK kinase kinase

NEMO:

NF-κB essential modifier

NF-κB:

Nuclear factor-kappaB

NIBP:

NIK-binding protein

NIK:

NF-κB-inducing kinase

Nod2:

Nucleotide-binding and oligomerization domain 2

PAN1:

PYRIN and NACHT domain protein 1

PDK1:

3-phosphoinositide-dependent kinase 1

PIDD:

p53-inducible death-domain-containing protein

PKC:

Protein kinase C

PKR:

Protein kinase double-stranded RNA-dependent

PMA:

Phorbol myristate acetate

RANK:

Receptor activator of NF-κB

RANKL:

Receptor activator of NF-κB ligand

RFP:

Ret finger protein

RIP1:

Receptor interacting protein 1

RSK:

Ribosomal S6 kinase

SAPK:

Stress activated protein kinase

SCF:

Skp1, Cdc53/Cullin1, F-box protein

Shh:

Sonic hedgehog

SMRT:

Silencing mediator for retinoic acid and thyroid hormone receptor

SRC-3:

Steroid receptor co-activator 3

STAP-2:

Signal-transducing adaptor protein-2

SUMO:

Small ubiquitin-like modifier

TAB:

Transforming growth factor-β activated kinase 1 binding protein

TACI:

Transmembrane activator and calcium modulator and cyclophilin ligand interactor

TAK1:

Transforming growth factor-β activated kinase 1

TANK:

TNF receptor associated factor family member-associated NF-κB activator

TCR:

T cell receptor

TFG:

Tyrosine receptor kinase-fused gene

TIFA:

TRAF-interacting protein with a forkhead-associated domain

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNF-R:

TNF receptor

TRADD:

TNF receptor-associated death domain

TRAF:

TNF receptor-associated factor

TRUSS:

TNF receptor-associated ubiquitous scaffolding and signaling protein

TWEAK:

TNF family member with weak apoptosis-inducing activity

vFLIP:

Viral FADD-like interleukin-1-β-converting enzyme (FLICE/caspase 8)-inhibitory protein

YopJ:

Yersinia outer protein J

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Acknowledgements

The author apologizes that many other relevant references could not be cited due to space constraints. The authors thank members of the laboratory, especially Drs Michael Hinz, Ruth Schmidt-Ullrich, Elmar Wegener and Buket Yilmaz, for critical comments on the manuscript. Work in the author's laboratory is supported by grants from the Bundesministerium für Bildung und Forschung and the Deutsche Forschungsgemeinschaft.

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Scheidereit, C. IκB kinase complexes: gateways to NF-κB activation and transcription. Oncogene 25, 6685–6705 (2006). https://doi.org/10.1038/sj.onc.1209934

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