RESUMO
The innate immune system needs to distinguish between harmful and innocuous stimuli to adapt its activation to the level of threat. How Drosophila mounts differential immune responses to dead and live Gram-negative bacteria using the single peptidoglycan receptor PGRP-LC is unknown. Here we describe rPGRP-LC, an alternative splice variant of PGRP-LC that selectively dampens immune response activation in response to dead bacteria. rPGRP-LC-deficient flies cannot resolve immune activation after Gram-negative infection and die prematurely. The alternative exon in the encoding gene, here called rPGRP-LC, encodes an adaptor module that targets rPGRP-LC to membrane microdomains and interacts with the negative regulator Pirk and the ubiquitin ligase DIAP2. We find that rPGRP-LC-mediated resolution of an efficient immune response requires degradation of activating and regulatory receptors via endosomal ESCRT sorting. We propose that rPGRP-LC selectively responds to peptidoglycans from dead bacteria to tailor the immune response to the level of threat.
Assuntos
Proteínas de Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Endossomos/metabolismo , Infecções por Bactérias Gram-Negativas/imunologia , Microdomínios da Membrana/metabolismo , Pectobacterium carotovorum/imunologia , Isoformas de RNA/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Transporte/metabolismo , Linhagem Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Éxons/genética , Técnicas de Inativação de Genes , Imunidade/genética , Imunomodulação , Proteínas Inibidoras de Apoptose/metabolismo , Ligação Proteica , Sinais Direcionadores de Proteínas/genética , Proteólise , Isoformas de RNA/genética , Relação Estrutura-AtividadeRESUMO
Caspases have been extensively studied as critical initiators and executioners of cell death pathways. However, caspases also take part in non-apoptotic signalling events such as the regulation of innate immunity and activation of nuclear factor-κB (NF-κB). How caspases are activated under these conditions and process a selective set of substrates to allow NF-κB signalling without killing the cell remains largely unknown. Here, we show that stimulation of the Drosophila pattern recognition protein PGRP-LCx induces DIAP2-dependent polyubiquitylation of the initiator caspase DREDD. Signal-dependent ubiquitylation of DREDD is required for full processing of IMD, NF-κB/Relish and expression of antimicrobial peptide genes in response to infection with Gram-negative bacteria. Our results identify a mechanism that positively controls NF-κB signalling via ubiquitin-mediated activation of DREDD. The direct involvement of ubiquitylation in caspase activation represents a novel mechanism for non-apoptotic caspase-mediated signalling.
Assuntos
Proteínas de Transporte/metabolismo , Caspases/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/imunologia , Regulação da Expressão Gênica , Bactérias Gram-Negativas/imunologia , Proteínas Inibidoras de Apoptose/metabolismo , Ubiquitinação , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Drosophila/genética , Drosophila/microbiologia , Imunidade Inata , Modelos Biológicos , NF-kappa B/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family, which activates c-Jun N-terminal kinase and p38 in response to a diverse array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. In the past decade, various regulatory mechanisms of ASK1 have been elucidated, including its oxidative stress-dependent activation. Recently, it has emerged that ASK family proteins play key roles in cancer, cardiovascular diseases and neurodegenerative diseases. In this review, we summarize the recent findings on ASK family proteins and their implications in various diseases.
RESUMO
Pattern recognition receptors are activated following infection and trigger transcriptional programs important for host defense. Tight regulation of NF-κB activation is critical to avoid detrimental and misbalanced responses. We describe Pickle, a Drosophila nuclear IκB that integrates signaling inputs from both the Imd and Toll pathways by skewing the transcriptional output of the NF-κB dimer repertoire. Pickle interacts with the NF-κB protein Relish and the histone deacetylase dHDAC1, selectively repressing Relish homodimers while leaving other NF-κB dimer combinations unscathed. Pickle's ability to selectively inhibit Relish homodimer activity contributes to proper host immunity and organismal health. Although loss of pickle results in hyper-induction of Relish target genes and improved host resistance to pathogenic bacteria in the short term, chronic inactivation of pickle causes loss of immune tolerance and shortened lifespan. Pickle therefore allows balanced immune responses that protect from pathogenic microbes while permitting the establishment of beneficial commensal host-microbe relationships.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Proteínas I-kappa B/metabolismo , Imunidade Inata , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Animais , Drosophila/imunologia , Proteínas de Drosophila/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Ligação Proteica , Mapeamento de Interação de ProteínasRESUMO
All aerobic organisms are exposed to oxidative stress during their lifetime and are required to respond appropriately for maintenance of their survival and homeostasis. Sustained exposure to oxidative stress has devastating effects in organisms, and, not surprisingly, oxidative stress has been implicated in numerous human diseases. Therefore, an understanding of how mammals respond to oxidative stress is crucial both biologically and clinically. Intracellular signaling pathways, which are activated in response to excessive oxygen radicals, play essential roles in overcoming oxidative stress. The mitogen-activated protein kinase (MAPK) signaling pathways are involved in diverse physiological processes, and are critical for induction of oxidative stress responses. In this review, we will discuss the physiological roles of MAPKs in oxidative stress, the upstream signaling pathways leading to MAPK activation, their regulation, and the MAPK downstream substrates, with a focus on mammalian systems.