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1.
Biomedicines ; 10(9)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36140409

RESUMO

Metazoans have developed strategies to protect themselves from pathogenic attack. These preserved mechanisms constitute the immune system, composed of innate and adaptive responses. Among the two kinds, the innate immune system involves the activation of a fast response. NF-κB signaling pathways are activated during infections and lead to the expression of timely-controlled immune response genes. However, activation of NF-κB pathways can be deleterious when uncontrolled. Their regulation is necessary to prevent the development of inflammatory diseases or cancers. The similarity of the NF-κB pathways mediating immune mechanisms in insects and mammals makes Drosophila melanogaster a suitable model for studying the innate immune response and learning general mechanisms that are also relevant for humans. In this review, we summarize what is known about the dynamic regulation of the central NF-κB-pathways and go into detail on the molecular level of the IMD pathway. We report on the role of the nuclear protein Akirin in the regulation of the NF-κB Relish immune response. The use of the Drosophila model allows the understanding of the fine-tuned regulation of this central NF-κB pathway.

2.
J Immunol ; 207(6): 1616-1626, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34452932

RESUMO

The evolutionarily conserved immune deficiency (IMD) signaling pathway shields Drosophila against bacterial infections. It regulates the expression of antimicrobial peptides encoding genes through the activation of the NF-κB transcription factor Relish. Tight regulation of the signaling cascade ensures a balanced immune response, which is otherwise highly harmful. Several phosphorylation events mediate intracellular progression of the IMD pathway. However, signal termination by dephosphorylation remains largely elusive. Here, we identify the highly conserved protein phosphatase 4 (PP4) complex as a bona fide negative regulator of the IMD pathway. RNA interference-mediated gene silencing of PP4-19c, PP4R2, and Falafel, which encode the catalytic and regulatory subunits of the phosphatase complex, respectively, caused a marked upregulation of bacterial-induced antimicrobial peptide gene expression in both Drosophila melanogaster S2 cells and adult flies. Deregulated IMD signaling is associated with reduced lifespan of PP4-deficient flies in the absence of any infection. In contrast, flies overexpressing this phosphatase are highly sensitive to bacterial infections. Altogether, our results highlight an evolutionarily conserved function of PP4c in the regulation of NF-κB signaling from Drosophila to mammals.


Assuntos
Proteínas de Drosophila/deficiência , Drosophila melanogaster/enzimologia , Drosophila melanogaster/imunologia , Imunidade Inata , NF-kappa B/metabolismo , Fosfoproteínas Fosfatases/deficiência , Transdução de Sinais/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Expressão Gênica , Inativação Gênica , Longevidade/genética , Longevidade/imunologia , Fosfoproteínas Fosfatases/genética , Interferência de RNA , Transdução de Sinais/genética , Regulação para Cima/genética
3.
PLoS Pathog ; 16(4): e1008458, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32339205

RESUMO

The Immune Deficiency (IMD) pathway in Drosophila melanogaster is activated upon microbial challenge with Gram-negative bacteria to trigger the innate immune response. In order to decipher this nuclear factor κB (NF-κB) signaling pathway, we undertook an in vitro RNAi screen targeting E3 ubiquitin ligases specifically and identified the HECT-type E3 ubiquitin ligase Hyperplastic discs (Hyd) as a new actor in the IMD pathway. Hyd mediated Lys63 (K63)-linked polyubiquitination of the NF-κB cofactor Akirin was required for efficient binding of Akirin to the NF-κB transcription factor Relish. We showed that this Hyd-dependent interaction was required for the transcription of immunity-related genes that are activated by both Relish and Akirin but was dispensable for the transcription of genes that depend solely on Relish. Therefore Hyd is key in NF-κB transcriptional selectivity downstream of the IMD pathway. Drosophila depleted of Akirin or Hyd failed to express the full set of genes encoding immune-induced anti-microbial peptides and succumbed to immune challenges. We showed further that UBR5, the mammalian homolog of Hyd, was also required downstream of the NF-κB pathway for the activation of Interleukin 6 (IL6) transcription by LPS or IL-1ß in cultured human cells. Our findings link the action of an E3 ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.


Assuntos
Proteínas de Drosophila/imunologia , Drosophila melanogaster/imunologia , Proteínas Nucleares/imunologia , Fatores de Transcrição/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Drosophila , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/microbiologia , Bactérias Gram-Negativas/fisiologia , Células HeLa , Humanos , Imunidade Inata , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
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