Year: 2014
Type: book-chapter
Abstract: COLOR PLATE 1 • (chapter 1) Comparison between Drosophila Toll and mammalian TLR4 and IL-1R receptor signaling pathways.(A) Binding of the maturated Spaetzle ligand triggers Toll signaling in Drosophila.A signaling complex, including MyD88, Tube, and Pelle, is recruited to the intracytoplasmic tail of the Toll receptor.This process is followed by the phosphorylation of the IkB-homolog Cactus by a so far unidentified kinase.Phosphorylated Cactus is degraded by the proteasome, allowing the nuclear translocation of the NF-kB transcription factors Dorsal and/or DIF (in larvae and adult flies respectively), activating the expression of hundreds of genes, including those encoding some of the antimicrobial peptides (Drosomycin).(B) A simplified scheme of TLR4 and IL-1R signaling pathways in mammals.(For a more detailed description the readers are referred to recent reviews by Bhoj and Chen, 2009; and Kawai and Akira, 2009).Upon stimulation by their corresponding ligands, TLR4 and IL-1R recruit a signaling complex comprising MyD88, IRAK1 and 4, and TRAF6, which controls the activation of TAK1.TAK1 further activates the IkB kinase (IKK) complex, which includes two catalytic subunits, IKKa and IKKb, and a regulatory subunit IKKg.Activated IKK phosphorylates IkB, which is further degraded by the proteasome.Freed NF-kB translocates to the nucleus and controls the expression of genes encoding inflammatory cytokines.MyD88, myeloid differentiation factor 88; IRAK, IL-IR associated kinase; TAK1, transforming growth factor (TGF)-b activated kinase 1; TRAF, tumor necrosis factor receptor (TNFR) associated factor; DD, death domain; KD, kinase domain. A BCOLOR PLATE 2 • (chapter 1) Comparison between the IMD pathway in Drosophila and the TNF-a receptor pathway in mammals.(A) Upon binding of DAP-type PGN to the PGRP-LC receptor, the adaptor protein IMD is recruited to the signaling domain of the receptor with which it interacts via a so far unidentified third partner.This process leads to the activation and nuclear translocation of the NF-kB transcription factor, Relish, driving the expression of hundreds of genes including those encoding some of the antimicrobial peptides such as Diptericin.Relish activation implies two independent processes activated downstream of the adaptor protein IMD.The first process involves FADD, the caspase-8 homolog DREDD, and TAK1, and leads to the phospho rylation of Relish by the IkB kinase (IKK) signalosome complex.This complex includes a regulatory subunit, Kenny (IKKg), and a catalytic subunit, ird5 (IKKb).The mechanism leading to the activation of TAK1 and IKK is currently unknown but probably involves K63-linked polyubiquitination mediated by the ubiquitin conjugating enzyme complex (Uev1a and Ubc13), the RING-domain containing protein DIAP2 (which possibly functions as a ubiquitin ligase), and TAB2, which contains a zinc finger which potentially binds to K63linked polyubiquitin chains.The second process involves FADD and DREDD (with a recently demonstrated input from the IKK complex) and leads to the cleavage of Relish, separating the C-terminal ankyrin repeat inhibitory domain from the Rel-containing segment.Note that TAK1 also serves to activate the JNK signaling pathway.(B) Signaling via the tumor necrosis factor-1 receptor (TNF-1R).(For a more detailed description the readers are referred to a recent review by Bhoj and Chen, 2009).Binding of TNFa to the TNF-1R leads to the recruitment of the death domain (DD) adaptor protein TRADD.A signaling complex is further assembled around TRADD, including RIP1, TRAF2, TRAF5, cIAP1, and cIAP2.RIP1 is a DD-containing serine/threonine kinase (DD similar to that of Drosophila IMD) and the TRAF and IAP proteins are RING-domain ubiquitin ligases.RIP1 is polyubiquitilated within this complex, a process that requires Ubc13 and Uev1A.The TAK1 kinase complex binds to the K63-linked polyubiquitin chains of RIP1 via TAB2/3.TAK1 is thus activated and phosphorylates the IKK complex.This complex includes two catalytic subunits, IKKa and IKKb, and a regulatory subunit, IKKg/NEMO, which mediates the binding of the IKK signalosome to the polyubiquitin chains.Activated IKK, in turn, phosphorylates IkB, which is further degraded by the proteasome.As a consequence, NF-kB translocates to the nucleus and activates the expression of numerous genes, namely those encoding inflammatory cytokines.Following the activation of NF-kB signaling, TRADD and RIP1 dissociate from the membrane receptor complex and associate with FADD, which binds to the caspase-8, forming a cytoplasmic complex that is implicated in signaling to apoptosis.cIAP, cellular inhibitor of apoptosis protein; DED, death effector domain; DIAP2, Drosophila inhibitor of apoptosis protein 2; DREDD, death-related ced-3/ nedd2-like protein; FADD, fas-associated death domain; NEMO, NF-kB essential modulator; TAK1, transforming growth factor (TGF)-activated kinase 1; TAB, TAK1 binding protein; Ubc13, ubiquitin-conjugating enzyme 13; Uev1a, ubiquitin-conjugating enzyme E2 variant; RING, really interesting new gene; RIP1, receptor interacting protein 1; TRADD, TNF-1R-associated via death domain; TRAF, TNFR-associated factor.
Source: ASM Press eBooks
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4249453118