Tuning innate immunity by translation

Rauscher, Robert; Ignatova, Zoya

doi:10.1042/bst20150166

Cited by 4 publications

(4 citation statements)

References 49 publications

(68 reference statements)

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“…S7B). Atf4 is a transcription factor for xCT linked to LPS-induced TLR4 signaling and cytokine production (36), and when phosphorylated, eIF2α is unable to bind to and inhibit Atf4 (37). eIF2α phosphorylation under AA-restricted conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dietary Protein Restriction Reprograms Tumor-Associated Macrophages and Enhances Immunotherapy

Orillion

Damayanti

Шен

et al. 2018

Clinical Cancer Research

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Diet and healthy weight are established means of reducing cancer incidence and mortality. However, the impact of diet modifications on the tumor microenvironment and antitumor immunity is not well defined. Immunosuppressive tumor-associated macrophages (TAMs) are associated with poor clinical outcomes and are potentially modifiable through dietary interventions. We tested the hypothesis that dietary protein restriction modifies macrophage function toward antitumor phenotypes. Macrophage functional status under different tissue culture conditions and was assessed by Western blot, immunofluorescence, qRT-PCR, and cytokine array analyses. Tumor growth in the context of protein or amino acid (AA) restriction and immunotherapy, namely, a survivin peptide-based vaccine or a PD-1 inhibitor, was examined in animal models of prostate (RP-B6Myc) and renal (RENCA) cell carcinoma. All tests were two-sided. Protein or AA-restricted macrophages exhibited enhanced tumoricidal, proinflammatory phenotypes, and in two syngeneic tumor models, protein or AA-restricted diets elicited reduced TAM infiltration, tumor growth, and increased response to immunotherapies. Further, we identified a distinct molecular mechanism by which AA-restriction reprograms macrophage function via a ROS/mTOR-centric cascade. Dietary protein restriction alters TAM activity and enhances the tumoricidal capacity of this critical innate immune cell type, providing the rationale for clinical testing of this supportive tool in patients receiving cancer immunotherapies.

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Section: Resultsmentioning

confidence: 99%

Dietary Protein Restriction Reprograms Tumor-Associated Macrophages and Enhances Immunotherapy

Orillion

Damayanti

Шен

et al. 2018

Clinical Cancer Research

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“…Instead, in planta the electron transfer from the FgNCP NO,TRI,ERG now takes part in DON production partly using the NO generating enzymes (see above). DON is an inhibitor of translation (Diamond et al ., 2013) and the innate immune responses in Eukaryotes are dependent on quick upregulation of defense protein (Rauscher and Ignatova, 2015). A shift from NO to DON production in planta to be able to attenuate eventually turned on plant defenses could be an evolutionary adaptation of F. graminearum .…”

Section: Resultsmentioning

confidence: 99%

“…The FgNCP NO,TRI,ERG has also been well described enzymatically under its UniProt entry name I1RZE7_GIBZE as a protein having all the necessary activities to take part in both DON and ergosterol synthesis 67 . DON is an inhibitor of translation 68 , and the innate immune responses in Eukaryotes depend on the quick upregulation of defence proteins 69 . A shift from NO to DON production in planta ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary conserved multifunctional nitric oxide synthesis proteins responding to bacterial MAMPs are located at the endoplasmic reticulum

Zheng

Ipcho

et al. 2020

Preprint

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Nitric oxide is known to be produced by most Eukaryotic organisms although the NO production mechanism is only known for animals (Canovas et al., 2016). Mammals have a set of different nitric oxide synthases (NOSs) with basically similar mechanism for producing NO under different circumstances (Velayutham and Zweier, 2013; Yu et al., 2014). NO-production is characteristically induced as part of innate immunity reactions to bacterial Microbial Associated Molecular Patterns (MAMPs). We knew from our previous work that the plant pathogen Fusarium graminearum quickly upregulate genes characteristic for an innate immune response so we set out to test if it also produces NO as part of this response and find the responsible genes if it does. We found that F. graminearum produces NO in response to bacterial MAMPs and that the NO production system must be similar in fungi as in mammals where NO is activated by a homo-dimerization of nitric oxide synthase proteins (NOSs) containing an N-terminal cytochrome P450 domain (CYP) and a C-terminal NADPH dependent cytochrome P450 reductase (NCP) domain. The electrons are transferred from the C-terminal NCP domains to the CYP domain in the paired protein to produce NO. We could not find a candidate NOS in the fungus. Thus, we tested the hypothesis that an NCP-protein similar to the NCP part of a NOS is brought together with a CYP-protein to produce NO in another way than the dimerization of a classic NOS. We found that in F. graminearum NO is produced by an FgNCP and an FgCYP located to the endoplasmic reticulum membrane where both proteins are predicted to be N-terminally attached by a transmembrane or embedded hydrophobic alpha helix. Deletion of any of these proteins lowered pathogenicity to wheat and stopped NO-production. Knockout of the FgNCP also completely blocked deoxynivalenol synthesis needed for pathogenicity indicating that the FgNCP also delivers electrons to another CYP (TRI4) located at the ER. The FgCYP we found to be involved in NO-productions is the same or similar to proteins involved in Eukaryote sterol synthesis (CYP51) reducing lanosterol on the way to the final main sterols different for different Eukaryotes. Lanosterol enriched membranes are known to be inhibited in endocytosis and we found that the deletion of the FgCYP producing NO also completely stopped endocytosis. We further tested consequences of these indications of more than one function and suggest the CYP-protein is most likely an FgCYPNO,ERG involved in both NO and ergosterol synthesis and the NCP is involved in NO, trichothecene and ergosterol synthesis, an FgNCPNO,TRI,ERG. The two proteins shown here to be responsible for NO production in F. graminearum are both highly conserved in Eukaryotes from amoeba to human and homologues are likely candidates for the production of NO in many other eukaryotes including mammals. The multiple functions of these proteins can be part of the explanation for the links between chronic inflammation, sterols and blood pressure in human.

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“…This highlights the necessity of a rapid and efficient innate response, balanced with appropriate transcriptional and post-transcriptional regulations that finely tune the underlying gene expression program. While transcriptional regulation clearly plays a major role during inflammation and has been widely studied as a model for cell stimulation (19,20), post-transcriptional control more recently emerged as indispensable to properly tune the innate response (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Shaping the Innate Immune Response Through Post-Transcriptional Regulation of Gene Expression Mediated by RNA-Binding Proteins

et al. 2022

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Innate immunity is the frontline of defense against infections and tissue damage. It is a fast and semi-specific response involving a myriad of processes essential for protecting the organism. These reactions promote the clearance of danger by activating, among others, an inflammatory response, the complement cascade and by recruiting the adaptive immunity. Any disequilibrium in this functional balance can lead to either inflammation-mediated tissue damage or defense inefficiency. A dynamic and coordinated gene expression program lies at the heart of the innate immune response. This expression program varies depending on the cell-type and the specific danger signal encountered by the cell and involves multiple layers of regulation. While these are achieved mainly via transcriptional control of gene expression, numerous post-transcriptional regulatory pathways involving RNA-binding proteins (RBPs) and other effectors play a critical role in its fine-tuning. Alternative splicing, translational control and mRNA stability have been shown to be tightly regulated during the innate immune response and participate in modulating gene expression in a global or gene specific manner. More recently, microRNAs assisting RBPs and post-transcriptional modification of RNA bases are also emerging as essential players of the innate immune process. In this review, we highlight the numerous roles played by specific RNA-binding effectors in mediating post-transcriptional control of gene expression to shape innate immunity.

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Tuning innate immunity by translation

Cited by 4 publications

References 49 publications

Dietary Protein Restriction Reprograms Tumor-Associated Macrophages and Enhances Immunotherapy

Dietary Protein Restriction Reprograms Tumor-Associated Macrophages and Enhances Immunotherapy

Evolutionary conserved multifunctional nitric oxide synthesis proteins responding to bacterial MAMPs are located at the endoplasmic reticulum

Shaping the Innate Immune Response Through Post-Transcriptional Regulation of Gene Expression Mediated by RNA-Binding Proteins

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