Dataset Information

Oyster Versatile IKK?/?s Are Involved in Toll-Like Receptor and RIG-I-Like Receptor Signaling for Innate Immune Response.

ABSTRACT: I?B kinases (IKKs) play critical roles in innate immunity through signal-induced activation of the key transcription factors nuclear factor-?B (NF-?B) and interferon regulatory factors (IRFs). However, studies of invertebrate IKK functions remain scarce. In this study, we performed phylogenetic analysis of IKKs and IKK-related kinases encoded in the Pacific oyster genome. We then cloned and characterized the oyster IKK?/?-2 gene. We found that oyster IKK?/?-2, a homolog of human IKK?/IKK?, responded to challenge with lipopolysaccharide (LPS), peptidoglycan (PGN), and polyinosinic-polycytidylic acid [poly(I:C)]. As a versatile immune molecule, IKK?/?-2 activated the promoters of NF-?B, TNF?, and IFN?, as well as IFN-stimulated response element (ISRE)-containing promoters, initiating an antibacterial or antiviral immune state in mammalian cells. Importantly, together with the cloned oyster IKK?/?-1, we investigated the signal transduction pathways mediated by these two IKK?/? proteins. Our results showed that IKK?/?-1 and IKK?/?-2 could interact with the oyster TNF receptor-associated factor 6 (TRAF6) and that IKK?/?-2 could also bind to the oyster myeloid differentiation factor 88 (MyD88) protein directly, suggesting that oyster IKK?/?s participate in both RIG-I-like receptor (RLR) and Toll-like receptor (TLR) signaling for the reception of upstream immune signals. The fact that IKK?/?-1 and IKK?/?-2 formed homodimers by interacting with themselves and heterodimers by interacting with each other, along with the fact that both oyster IKK?/? proteins interacted with NEMO protein, indicates that oyster IKK?/?s and the scaffold protein NEMO form an IKK complex, which may be a key step in phosphorylating I?B proteins and activating NF-?B. Moreover, we found that oyster IKK?/?s could interact with IRF8, and this may be related to the IKK-mediated activation of ISRE promotors and their involvement in the oyster "interferon (IFN)-like" antiviral pathway. Moreover, the expression of oyster IKK?/?-1 and IKK?/?-2 may induce the phosphorylation of I?B proteins to activate NF-?B. These results reveal the immune function of oyster IKK?/?-2 and establish the existence of mollusk TLR and RLR signaling mediated by IKK?/? proteins for the first time. Our findings should be helpful in deciphering the immune mechanisms of invertebrates and understanding the development of the vertebrate innate immunity network.

SUBMITTER: Huang B

PROVIDER: S-EPMC6685332 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Oyster Versatile IKKα/βs Are Involved in Toll-Like Receptor and RIG-I-Like Receptor Signaling for Innate Immune Response.

Huang Baoyu B Zhang Linlin L Xu Fei F Tang Xueying X Li Li L Wang Wei W Liu Mingkun M Zhang Guofan G

Frontiers in immunology 20190731

IκB kinases (IKKs) play critical roles in innate immunity through signal-induced activation of the key transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs). However, studies of invertebrate IKK functions remain scarce. In this study, we performed phylogenetic analysis of IKKs and IKK-related kinases encoded in the Pacific oyster genome. We then cloned and characterized the oyster IKKα/β-2 gene. We found that oyster IKKα/β-2, a homolog of h ...[more]

PMID: 31417578

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Project description:Retinoic-acid-inducible gene-I (RIG-I; also known as DDX58) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (PAMP) motifs to differentiate between viral and cellular RNAs. RIG-I is activated by blunt-ended double-stranded (ds)RNA with or without a 5'-triphosphate (ppp), by single-stranded RNA marked by a 5'-ppp and by polyuridine sequences. Upon binding to such PAMP motifs, RIG-I initiates a signalling cascade that induces innate immune defences and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signalling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases and cancer. The helicase and repressor domains (RD) of RIG-I recognize dsRNA and 5'-ppp RNA to activate the two amino-terminal caspase recruitment domains (CARDs) for signalling. Here, to understand the synergy between the helicase and the RD for RNA binding, and the contribution of ATP hydrolysis to RIG-I activation, we determined the structure of human RIG-I helicase-RD in complex with dsRNA and an ATP analogue. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle X-ray scattering, limited proteolysis and differential scanning fluorimetry indicate that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the role of helicase in dsRNA recognition, the synergy between the RD and the helicase for RNA binding and the organization of full-length RIG-I bound to dsRNA, and provide evidence of a conformational change upon RNA binding. The RIG-I helicase-RD structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yields unprecedented insight into innate immunity and has a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains within DICER and FANCM.

Dataset Information

Oyster Versatile IKK?/?s Are Involved in Toll-Like Receptor and RIG-I-Like Receptor Signaling for Innate Immune Response.

Publications

Oyster Versatile IKKα/βs Are Involved in Toll-Like Receptor and RIG-I-Like Receptor Signaling for Innate Immune Response.

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