Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

The IκB kinases (IKKs) IKK-α and IKK-β, and the IKK-related kinases TBK1 and IKK-ɛ, have essential roles in innate immunity through signal-induced activation of NF-κB, IRF3 and IRF7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NF-κB essential modulator coordinates some IKK complexes, whereas TANK, NF-κB-activating kinase-associated protein 1 (NAP1) or similar to NAP1 TBK1 adaptor (SINTBAD) assemble TBK1 and IKK-ɛ complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence indicates that distinct scaffold proteins assemble IKK, and potentially TBK1 and IKK-ɛ subcomplexes, in a stimulus-specific manner, which might be a mechanism to achieve specificity. *Authors contributed equally to this work. The IκB kinases (IKKs) IKK-α and IKK-β, and the IKK-related kinases TBK1 and IKK-ɛ, have essential roles in innate immunity through signal-induced activation of NF-κB, IRF3 and IRF7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NF-κB essential modulator coordinates some IKK complexes, whereas TANK, NF-κB-activating kinase-associated protein 1 (NAP1) or similar to NAP1 TBK1 adaptor (SINTBAD) assemble TBK1 and IKK-ɛ complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence indicates that distinct scaffold proteins assemble IKK, and potentially TBK1 and IKK-ɛ subcomplexes, in a stimulus-specific manner, which might be a mechanism to achieve specificity. *Authors contributed equally to this work. the CARD is found in some initiator caspases, but also in some adaptor proteins, and mediates protein–protein interactions. the classical pathway is triggered by various stimuli, including proinflammatory cytokines and TLR ligands, and leads to the activation of the IKK complex that includes IKK-α and IKK-β and also the scaffold protein NEMO. This complex targets the inhibitory IκBα protein for phosphorylation, which is followed by its degradation through the proteasome pathway. NF-κB heterodimers (typically composed of p50 and p65) subsequently move into the nucleus to drive the expression of proinflammatory molecules and chemokines. The alternative pathway is triggered by stimuli such as lymphotoxin-β and requires the kinase NIK in addition to an IKK-α homodimer. NEMO is dispensable for this pathway to be activated. The targeted inhibitory molecule is p100 instead of IκBα, and the NF-κB heterodimers are typically composed of p52 and RelB. The target genes of this pathway are required for adaptive immunity. dendritic cells (DCs) take up antigens, are activated and migrate to lymphoid tissues in order to present the antigenic peptides on the MHC molecules. They can be broadly divided into plasmacytoid DCs (pDCs) and conventional myeloid DCs, based on the expression of a variety of cell surface markers and their responses to pathogen molecules. pDCs are defined as a subset of cells, the appearance under the microscope of which is similar to that of plasmablasts. These cells are the main producers of type I IFNs in response to viral infections. CpG DNAs are DNA oligodeoxynucleotide sequences that include a cytosine–guanosine sequence and some flanking nucleotides. The CpG DNAs induce innate immunity through binding to the TLR9 receptor. these pathways include the RIG-I family (comprising MDA5 and RIG-I) and are triggered following infection with RNA viruses and also the DAI-dependent pathway, which is activated when this cytosolic receptor senses DNA from viruses or damaged cells. E3 ligases are defined as enzymes that facilitate the transfer of the ubiquitin from the ubiquitin-conjugating enzyme (E2) to the ɛ-amino group of a lysine residue in a target protein. innate immunity is defined as the initial, rapidly induced immune response of most multicellular organisms. This immunity relies on receptors required for pathogen recognition and the recruitment and activation of phagocytic cells. IFNs are defined as cytokines that block viral replication and infection of surrounding cells. IRFs are a family of nine proteins (IRF1 to IRF9) that share a well-conserved DNA-binding domain of ∼120 amino acids at their N-terminus. This domain is required to bind to the consensus DNA sequence that is known as the ISRE. IRFs are involved in the development and function of immune cells. IRF3 and IRF7 are activated through TBK1 and IKK-ɛ-mediated phosphorylation on their C-terminal domain. ISRE is a DNA motif that is bound by IRFs. The consensus sequence is GAAANNGAAAG/CT/C, where N denotes any nucleotide. LPS is a component of the outer membrane of Gram-negative bacteria and triggers NF-κB and IRF activation through binding to the TLR4 receptor. NEMO is required to assemble IKK-α and IKK-β into an IκBα-phosphorylating complex following stimulation by various stimuli, including proinflammatory cytokines and molecular components of pathogens. NF-κB is a structurally and evolutionarily conserved family of transcription factors initially identified as proteins harboring a DNA-binding activity for the enhancer of the immunoglobulin κ light-chain in activated B cells. These proteins are crucial for the production of proinflammatory cytokines, growth factors and enzymes required for the initiation and resolution of the immune response. These proteins include RelA (also known as p65), RelB, c-Rel and also p50 and p52 (which are generated from processed precursors – namely, p105 and p100, respectively). a molecular pattern which is found in microorganisms but not in host cells. a scaffold protein is referred to as a molecule that functions as a platform in order to promote the recruitment and assembly of complexes. These proteins do not harbor any enzymatic activity but are nevertheless essential for the activation of the enzymes to which they bind. the TIR domain is defined as an amino acid sequence of the cytoplasmic region that is highly conserved among members of the TLR and IL-1 receptor superfamily. a family of proteins that includes IFN-α and IFN-β. the post-translational modification of proteins by the attachment of one or more 7kDa ubiquitin molecules to lysine residues of the substrates. This modification triggers protein degradation (K48-linked polyubiquitylation) or is required for cell signaling (K63-linked polyubiquitylation).