The Function of Receptor-interacting Protein（RIP）Kinases and the Research Progress in Teleost Fish

doi:10.13560/j.cnki.biotech.bull.1985.2020-1258

Abstract

Abstract:

Receptor-interacting protein（RIP）kinases are key regulators that mediate cell death signals and inflammatory responses,and play vital roles in regulating immune responses and maintaining organism homeostasis. RIP kinases are involved in different biological processes such as cell death,inflammatory responses,and innate immunity in mammals. However,fish is an important group of vertebrates and our knowledge about the function of RIP kinases in fish is still limited. Therefore,this article mainly reviews the molecular structure,mediated signaling pathways and mechanisms of RIP family members,as well as the research progress of that in teleost fish,aiming to lay a foundation for deeply understanding immune responses and resistance mechanisms in fish as well as in mammals.

Key words: receptor-interacting protein, innate immunity, cell death, inflammatory response

LI Kai-qing, LI Ying, WANG Yi-lei, ZOU Peng-fei. The Function of Receptor-interacting Protein（RIP）Kinases and the Research Progress in Teleost Fish[J]. Biotechnology Bulletin, 2021, 37(5): 197-211.

Figures/Tables 4

Fig. 1 Protein domain of mammalian RIP family members KD stands for kinase domain, RHIM stands for receptor-interacting-protein homotypic interaction motif, DD stands for death domain, CARD stands for caspase activation and recruitment domain, ANK stands for ankyrin repeat, Roc/CoR stands for ras complex protein/C-terminal of Roc, LRR leucine-rich repeat

Fig. 2 RIP1 and RIP3-mediated signaling pathways in mammals RIP1 is recruited via the adaptor protein TRADD to the TNFR1 upon the stimulation of TNF-α, and then activates NF-κB signaling pathway to mediate inflammation and initiates caspase-dependent cell apoptosis. The dsRNA and LPS could be recognized by TLR3 and TLR4, respectively, which then recruit the adaptor molecule TRIF to interact with RIP1, and then associate with TRAF6 to participate in the activation of downstream NF-κB signals, thereby inducing the transcription of pro-inflammatory cytokines. RIP1 mediates cell apoptosis by binding to FADD and caspase-8 to form a death complex. When the activity of caspase-8 is inhibited, the assembly of RIP1-RIP3-MLKL necrosomes mediates cell necrosis, and then RIP3 activates inflammasomes to mediate cell pyrotosis. LPS stands for Lipopolysaccharide. TNF-α stands for Tumor necrosis factor alpha. TNFR1 stands for TNF-receptor 1. TRADD stands for TNF-receptor-associated death domain. TRAF stands for TNF receptor associated factor. cIAPs stands for Cellular inhibitor of apoptosis proteins. FADD stands for Fas-associated death domain. NF-κB stands for Nuclear transcription factor-κB. TLR stands for Toll-like receptor. TRAM stands for TIR domain-containing adaptor-inducing IFNβ-related adaptor molecule. TRIF stands for TIR domain-containing adaptor-inducing IFNβ. NLRP3 stands for NOD-like receptor family pyrin domain containing 3. ASC stands for Apoptosis-associated speck-like protein containing CARD. IL-1 stands for Interleukin-1

Fig. 3 RIP2-mediated signaling pathways in mammals RIP2 is recruited and activated by NOD1 and NOD2, which recognize iE-DAP and MDP, respectively, thereby activating TAB-TAK and IKK complexes and inducing activation of NF-κB and MAPK signaling pathways. TRIP6 and RIP7 positively regulate NOD1/2-RIP2 mediated signaling pathway, whereas caspase-12, A20, OTULIN and CYLD negatively regulate the NOD1/2-RIP2 mediated signaling pathway. RIP2 can interact with caspase-1 to mediate the activation of NF-κB, whereas ASC competes with RIP2 to inhibit the activation of NF-κB by caspase-1 and promotes the processing of proinflammatory cytokines. iE-DAP stands for γ-d-glutamyl-meso-diaminopimelic acid. MDP stands for muramyl dipeptide. NOD stands for nucleotide-binding oligomerization domains. XIAP stands for X-linked inhibitor of apoptosis protein. TRIP6 stands for thyroid hormone receptor interactor 6. CYLD stands for cylindromatosis. TAK stands for TGFβ-activated kinase. TAB stands for TGFβ-activated kinase binding protein. IKK stands for inhibitor of nuclear factor kappa-B kinase. and MAPK stands for mitogen-activated protein kinase

Fig. 4 RIP1, RIP2, and RIP3-mediated signaling pathways in teleosts RIP1 is involved in activation of TLR3, TLR19, and TLR22 mediated NF-κB signaling pathway through interaction with TRIF, and also activates TBK1 and IKKε-mediated production of IFN by binding to downstream TRAF3 in teleosts. Recognition of viral dsRNA activates RIG-I and MDA5, which then mediate downstream IRF3 and IRF7 signal transduction through the adaptor molecule MAVS, whereas RIP1 negatively regulates MAVS-mediated RLRs antiviral signal pathway. The combination of RIP1, TRAD and TRAF2 activates NF-κB signaling pathway and mediates cell apoptosis upon the stimulation of TNF-α. RIP1 form necrosomes with RIP3 and MLKL to induce cell necrosis. RIP2 interacts with NOD1/2 to activate the TAB-TAK1 and IKK complexes and induce the activation of the NF-κB signaling pathway to promote the production of proinflammatory cytokines. RIP2 is involved in MHC antigen presentation and autophagy. RIG-Ⅰstands for retinoic acid-inducible geneⅠ. MDA5 stands for melanoma differentiation associated gene 5. MAVS stands for mitochondrial antiviral-signaling protein. MHC stands for major histocompatibility complex. TBK1 stands for TANK binding kinase 1. IRF3 stands for interferon regulatory factor 3. IRF7 stands for interferon regulatory factor 7. and ISGs stands for interferon stimulated genes

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