Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

Abstract

A large body of literature describes elaborate NF-κB signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-κB dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-κB dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-κB is also responsive to genotoxic agents; however, signal communication networks that are initiated in the nucleus following DNA damage induction are less defined. Evidence in the literature supports the presence of such signaling pathways induced by multiple distinct genotoxic agents, resulting in the activation of cytoplasmic IKK complex. An example is a pathway that involves the DNA damage-responsive kinase ataxia telangiectasia mutated (ATM) and a series of post-translational modifications of NF-κB essential modulator (NEMO) in the nucleus of a genotoxin-exposed cell. Recent evidence also suggests that this nuclear-initiated NF-κB signaling pathway plays significant physiological and pathological roles, particularly in lymphocyte development and human cancer progression. This review will summarize these new developments, while identifying significant unanswered questions and providing new hypotheses that may be addressed in future studies.

Figure 1

Complexity of signal initiation event(s) in NF-κB signaling induced by gentoxic agents. The ligand-receptor interaction represents the signal initiation event for NF-κB activation induced by a traditional canonical NF-κB inducer, such as TNFα (left). Genotoxic agents, such as IR (ionizing radiation), may induce different types of nuclear DNA damage and stress conditions, as well as induce other cellular stress conditions (right). Different DNA and cell stress conditions listed as examples are not meant to be comprehensive. The fundamental knowledge of the necessary and sufficient events that initiate NF-κB signaling pathways induced by genotoxic agents is currently incomplete. Because of the presence of concurrent molecular events induced by different genotoxic agents, more than one mechanism may be induced to control NF-κB activation with varying dominance and different kinetics.

Figure 2

A model depicting distinct and common steps between NF-κB signaling induced by TNFα and DNA damaging agents. TNFα stimulation of TNFR1 engages receptor adaptor proteins (TRADD and RIP1) and results in the recruitment of ubiquitin conjugating enzymes (Ubc13/Uev1A and UbcH5) and E3 ligases (cIAP1/2, TRAF2/5 and HOIL/HOIP) to promote K63-linked, mixed and linear polyubiquitination of multiple target proteins. These polyubiquitin chains form the scaffold on which TAK1/TAB2/3 and IKK/NEMO complexes are formed and TAK1-dependent activation of IKKβ is induced. DNA damaging agents, such as etoposide, cause ATM activation via induction of DSB and SUMOylation of NEMO through a mechanism dependent on PARP1, PIASy and Ubc9. PIASy dependent SUMOylation of NEMO may also be induced by additional stress conditions. ATM then phosphorylates NEMO, which results in cIAP1-dependent monoubiquitination of NEMO. ATM and NEMO are exported to the cytoplasm where K63-linked polyubiquitination of ELKS and TRAF6 via ATM-dependent mechanism, as well as monoubiquitination of NEMO on lysine 285 via cIAP1, are induced. The polyubiquitin scaffolds then activate IKK via TAK1, similar to the mechanism induced by TNFα. Active IKK then phosphorylates IκBα, which then causes K48-linked polyubiquitination and degradation of IκBα by the proteasome to liberate active NF-κB (p50/p65) dimer. Polyubiquitin is represented in repeated yellow units, phosphate is shown in orange oval with “P” and SUMOylation is shown in purple circle with “S”. LUBAC, linear ubiquitin assembling complex.