周芳:Crosstalk in NF

Crosstalk in NF-κB signaling pat
NF-κB transcription factors are critical regulators of immunity, stress responses, apoptosis and differentiation. A variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied transcriptional programs. Consequently, NF-κB-dependent transcription is not only tightly controlled by positive and negative regulatory mechanisms but also closely coordinated with other signaling pathways. This intricate crosstalk is crucial to shaping the diverse biological functions of NF-κB into cell type– and context-specific responses.
Figures at a glance
left Figure 1: Canonical and noncanonical pathways of NF-κB activation.
Under resting conditions, NF-κB dimers are bound to inhibitory IκB proteins, which sequester inactive NF-κB complexes in the cytoplasm. Stimulus-induced degradation of IκB proteins is initiated through phosphorylation by the IκB kinase (IKK) complex, which consists of two catalytically active kinases, IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO). Phosphorylated IκB proteins are targeted for ubiquitination and proteasomal degradation, which thus releases the bound NF-κB dimers so they can translocate to the nucleus. NF-κB signaling is often divided into two types of pathways. The canonical pathway (left) is induced by most physiological NF-κB stimuli and is represented here by TNFR1 signaling. Stimulation of TNFR1 leads to the binding of TRADD, which provides an assembly platform for the recruitment of FADD and TRAF2. TRAF2 associates with RIP1 for IKK activation. In the canonical pathway (right), IκBα is phosphorylated in an IKKβ- and NEMO-dependent manner, which results in the nuclear translocation of mostly p65-containing heterodimers. Transcriptional activity of nuclear NF-κB is further regulated by PTM. In contrast, the noncanonical pathway, induced by certain TNF family cytokines, such as CD40L, BAFF and lymphotoxin-β (LT-β), involves IKKα-mediated phosphorylation of p100 associated with RelB, which leads to partial processing of p100 and the generation of transcriptionally active p52-RelB complexes. IKKα activation and phosphorylation of p100 depends on NIK, which is subject to complex regulation by TRAF3, TRAF2 and additional ubiquitin ligases. LT-βR, receptor for lymphotoxin-β.
Figure 2: TRAF- and RIP1-dependent signaling pathways.
(a) TRAF-dependent signaling pathways. TRAFs function downstream of many various receptors and promote the activation of AP-1 and NF-κB transcription factors. Also, several receptors can use more than one TRAF protein for signal transduction, which allows combinatorial specification of signaling outcomes. The function of TRAF2 and TRAF5 is best characterized in TNFR1 signaling, whereas TRAF6 and TRAF3 have been extensively studied in IL-1R or TLR signaling and in noncanonical NF-κB signaling, respectively. Each receptor and the signaling pathway(s) it induces are in a similar color. In addition to its role in noncanonical NF-κB signaling (green), TRAF3 has been demonstrated to be critical for virus-induced activation of IRF3-IRF7 and interferon production (yellow). TRAF2 is involved in signaling downstream of CD40 or the BAFF receptor BAFF-R through the regulation of TRAF3 stability and activation of AP-1 and NF-κB. TRAF2 and TRAF5 mediate canonical activation of NF-κB and AP-1 in response to TNF and other proinflammatory cytokines (blue). Downstream of IL-1R and TLR, this role is exerted by TRAF6 (orange). After engagement of TLR1, TLR2 or TLR4, TRAF6 also translocates to mitochondria, where it binds to ECSIT to induce mitochondrial ROS (mROS) and enhance bacterial killing. In osteoclasts, TRAF6 has also been shown to function in signaling via the TRANCE receptor TRANCE-R by mediating activation of c-Src (purple). In addition, TRAF2 has been shown to inhibit IL-4 and T helper type 2 differentiation of T cells by negatively regulating the NFAT-interacting protein NIP45 (gray). (b) RIP1-dependent signaling pathways. Through its involvement in the regulation of survival (Complex I), apoptosis (Complex II) and necroptosis (Necrosome), RIP1 is positioned at the center of cell-fate 'decisions'. After stimulation with TNF, rapid assembly of complex I (containing TRADD, RIP1 and TRAF2) occurs at the receptor, which triggers NF-κB activation through recruitment of the IKK complex. In the course of signal transduction, TRADD-RIP1-TRAF2 dissociates from the receptor, binding FADD and caspases to induce apoptosis. The deubiquitinase CYLD has been demonstrated to promote apoptosis and/or necroptosis by enhancing the RIP1-FADD interaction, which suggests that the ubiquitination status of RIP1 may 'tune' its activity in different pathways. When caspase activation is inhibited, such as during certain viral infections, RIP1 acts with RIP3 to induce necroptosis. RIP1-RIP3 transphosphorylation leads to RIP3-dependent production of ROS, which contributes to necroptotic cell death. Furthermore, RIP1 has been suggested to be involved in activation of the PI(3)K-Akt pathway through NF-κB-independent downregulation of PTEN and to influence EGFR expression through its action as a negative regulator of the transcription factor Sp-1. Bad, Bcl-xL–Bcl-2–associated death promotor.
Figure 3: NF-κB-independent functions of IKK complex subunits.