Martí López‐Serrat

Universitat de Barcelona

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Jorge Lloberas

Universitat de Barcelona

Lorena Valverde‐Estrella

Universitat de Barcelona

Antonio Celada

Universitat de Barcelona

Guillem Sánchez‐Sànchez

Universitat de Barcelona

Carlos Batlle

Universitat de Barcelona

Iris Aparici‐Herraiz

Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol

Tania Vico

Universitat de Barcelona

Pere Rehues

Institut d'Investigació Sanitària Pere Virgili

Guillem Sanchez Sanchez

Université Libre de Bruxelles

Guadalupe Sánchez-Sánchez

Hospital General Universitario de Alicante Doctor Balmis

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Universitat de Barcelona

Institute for Research in Biomedicine

Barcelona Biomedical Research Park

Vitenparken

Institut d'Investigacions Biomèdiques de Barcelona

Biomedical Research Institute

Bedford Research Foundation

Clínica Diagonal

Universitat Autònoma de Barcelona

Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol

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Supplementary Material for: IRF1 Is Required for MDA5 (IFIH1) Induction by IFN-α, LPS, and poly(I:C) in Murine Macrophages

Figshare (2022)

Iris Aparici‐Herraiz Guadalupe Sánchez-Sánchez Carlos Batlle Pere Rehues Martí López‐Serrat

Melanoma differentiation-associated protein 5 (MDA5) induces type I interferons (IFNs) after the recognition of viral RNA. In addition, gain-of-function mutations in the interferon induced with helicase C domain 1 (IFIH1) gene, which encodes MDA5, lead to type I interferonopathies. Here, we show that Mda5 is highly expressed in murine macrophages and is regulated by pro-inflammatory stimuli such as the cytokines IFN-α and IFN-γ, the TLR ligand LPS, and a mimic of dsRNA, poly(I:C). Mda5 induction is mediated through the production of reactive oxygen species. The induction by IFN-α or LPS occurs at the transcriptional level since the Mda5 mRNA half-life before and after induction is very stable. Interestingly, STAT1 is required for Mda5 induction by IFN-α, LPS, or poly(I:C). The time course of induction of at least 3 h and the need for protein synthesis indicate that Mda5 requires an intermediate protein for transcription. In transient transfection experiments, we found that a 105-bp fragment of this gene, between −1153 and −1258 bp relative to the transcription start site, is required for transcription. In this specific region, we observed a sequence containing an IRF-binding motif, which, when mutated, abolishes the induction of Mda5. This sequence is strongly conserved in the IFIH1 promoters of eutherian mammals and in other distant species. Kinetic experiments, chromatin immunoprecipitation assays, and gene-silencing experiments revealed that IRF1 is required for induction of Mda5 expression.

MDA5

IRF1

10.6084/m9.figshare.21557808

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Author response for "Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1"

Lorena Valverde‐Estrella Martí López‐Serrat Guillem Sánchez‐Sànchez Tania Vico Jorge Lloberas

IRF1

SAMHD1

Interferon γ

10.1002/eji.201948491/v2/response1

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Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1

European Journal of Immunology (2020)

Lorena Valverde‐Estrella Martí López‐Serrat Guillem Sánchez‐Sànchez Tania Vico Jorge Lloberas

Abstract SAMHD1 is an enzyme with phosphohydrolase activity. Mutations in SAMHD1 have been linked to the development of Aicardi‐Goutières syndrome in humans. This enzyme also has the capacity to restrict HIV virus replication in macrophages. Here, we report that Samhd1 is highly expressed in murine macrophages and is regulated by proinflammatory (IFN‐γ and LPS) but not by anti‐inflammatory (IL‐4 or IL‐10) activators. The induction of Samhd1 follows the pattern of an intermediate gene that requires protein synthesis. In transient transfection experiments using the Samhd1 promoter, we found that a fragment of 27 bps of this gene, falling between −937 and −910 bps relative to the transcription start site, is required for IFN‐γ‐dependent activation. Using EMSAs, we determined that IFN‐γ treatment led to the elimination of a protein complex. Chromatin immunoprecipitation assays and siRNA experiments revealed that IRF1 is required for IFN‐γ‐ or LPS‐induced Samhd1 expression. Therefore, our results indicate that Samhd1 is stimulated by proinflammatory agents IFN‐γ and LPS. Moreover, they reveal that these two agents, via IRF1, eliminate a protein complex that may be related to a repressor, thereby, triggering Samhd1 expression.

IRF1

SAMHD1

Gamma interferon

Interferon γ

10.1002/eji.201948491

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IRF1 Is Required for MDA5 (IFIH1) Induction by IFN-α, LPS, and poly(I:C) in Murine Macrophages

Journal of Innate Immunity (2022)

Iris Aparici‐Herraiz Guillem Sanchez Sanchez Carlos Batlle Pere Rehues Martí López‐Serrat

Melanoma differentiation-associated protein 5 (MDA5) induces type I interferons (IFNs) after the recognition of viral RNA. In addition, gain-of-function mutations in the interferon induced with helicase C domain 1 (IFIH1) gene, which encodes MDA5, lead to type I interferonopathies. Here, we show that Mda5 is highly expressed in murine macrophages and is regulated by pro-inflammatory stimuli such as the cytokines IFN-α and IFN-γ, the TLR ligand LPS, and a mimic of dsRNA, poly(I:C). Mda5 induction is mediated through the production of reactive oxygen species. The induction by IFN-α or LPS occurs at the transcriptional level since the Mda5 mRNA half-life before and after induction is very stable. Interestingly, STAT1 is required for Mda5 induction by IFN-α, LPS, or poly(I:C). The time course of induction of at least 3 h and the need for protein synthesis indicate that Mda5 requires an intermediate protein for transcription. In transient transfection experiments, we found that a 105-bp fragment of this gene, between -1153 and -1258 bp relative to the transcription start site, is required for transcription. In this specific region, we observed a sequence containing an IRF-binding motif, which, when mutated, abolishes the induction of Mda5. This sequence is strongly conserved in the IFIH1 promoters of eutherian mammals and in other distant species. Kinetic experiments, chromatin immunoprecipitation assays, and gene-silencing experiments revealed that IRF1 is required for induction of Mda5 expression.

MDA5

Chromatin immunoprecipitation

Transcription

IRF1

10.1159/000527008

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Citations (3)