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Caspase-Dependent Cleavage of DDX21 Suppresses Host Innate Immunity.

ABSTRACT: DEAD (Glu-Asp-Ala-Glu) box RNA helicases have been proven to contribute to antiviral innate immunity. The DDX21 RNA helicase was identified as a nuclear protein involved in rRNA processing and RNA unwinding. DDX21 was also proven to be the scaffold protein in the complex of DDX1-DDX21-DHX36, which senses double-strand RNA and initiates downstream innate immunity. Here, we identified that DDX21 undergoes caspase-dependent cleavage after virus infection and treatment with RNA/DNA ligands, especially for RNA virus and ligands. Caspase-3/6 cleaves DDX21 at D126 and promotes its translocation from the nucleus to the cytoplasm in response to virus infection. The cytoplasmic cleaved DDX21 negatively regulates the interferon beta (IFN-β) signaling pathway by suppressing the formation of the DDX1-DDX21-DHX36 complex. Thus, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immune response to virus. IMPORTANCE Innate immunity serves as the first barrier against virus infection. DEAD (Glu-Asp-Ala-Glu) box RNA helicases, originally considered to be involved in RNA processing and RNA unwinding, have been shown to play an important role in antiviral innate immunity. The precise regulation of innate immunity is critical for the host because the aberrant production of cytokines leads to unexpected pathological consequences. Here, we identified that DDX21 was cleaved at D126 by virus infection and treatment with RNA/DNA ligands via the caspase-3/6-dependent pathway. The cytoplasmic cleaved DDX21 negatively regulates the IFN-β signaling pathway by suppressing the formation of the DDX1-DDX21-DHX36 complex. In sum, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immune response to virus.

SUBMITTER: Wu W

PROVIDER: S-EPMC8262918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledInterleukin-1? (IL-1?) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1?; however, the host and parasite factors that mediate IL-1? production during T. gondii infection are poorly understood. We report that T. gondii induces IL-1? transcript, processing/cleavage, and release from infected primary human monocytes and THP-1 cells. Treating monocytes with the caspase-1 inhibitor Ac-YVAD-CMK reduced IL-1? release, suggesting a role for the inflammasome in T. gondii-induced IL-1? production. This was confirmed by performing short hairpin RNA (shRNA) knockdown of caspase-1 and of the inflammasome adaptor protein ASC. IL-1? induction required active parasite invasion of monocytes, since heat-killed or mycalolide B-treated parasites did not induce IL-1?. Among the type I, II, and III strains of T. gondii, the type II strain induced substantially more IL-1? mRNA and protein release than did the type I and III strains. Since IL-1? transcript is known to be induced downstream of NF-?B signaling, we investigated a role for the GRA15 protein, which induces sustained NF-?B signaling in a parasite strain-specific manner. By infecting human monocytes with a GRA15-knockout type II strain and a type I strain stably expressing type II GRA15, we determined that GRA15 is responsible for IL-1? induction during T. gondii infection of human monocytes. This research defines a pathway driving human innate immunity by describing a role for the classical inflammasome components caspase-1 and ASC and the parasite GRA15 protein in T. gondii-induced IL-1? production.ImportanceMonocytes are immune cells that protect against infection by increasing inflammation and antimicrobial activities in the body. Upon infection with the parasitic pathogen Toxoplasma gondii, human monocytes release interleukin-1? (IL-1?), a "master regulator" of inflammation, which amplifies immune responses. Although inflammatory responses are critical for host defense against infection, excessive inflammation can result in tissue damage and pathology. This delicate balance underscores the importance of understanding the mechanisms that regulate IL-1? during infection. We have investigated the molecular pathway by which T. gondii induces the synthesis and release of IL-1? in human monocytes. We found that specific proteins in the parasite and the host cell coordinate to induce IL-1? production. This research is significant because it contributes to a greater understanding of human innate immunity to infection and IL-1? regulation, thereby enhancing our potential to modulate inflammation in the body.

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Caspase-Dependent Cleavage of DDX21 Suppresses Host Innate Immunity.

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