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TENT5 cytoplasmic non-canonical poly(A) polymerases regulate the innate immune response in animals

ABSTRACT: Innate immunity, the first line of host defense against pathogens, is tightly regulated both transcriptionally and post-transcriptionally. Here, through global transcriptome and proteome analyses in Caenorhabditis elegans, we uncover a modulation of the expression of secreted innate immunity effector proteins by TENT5, one of a recently described family of cytoplasmic poly(A) polymerases. Direct RNA sequencing revealed that TENT-5 polyadenylates mRNAs with signal peptide-encoding sequences, that are translated at the endoplasmic reticulum. Loss of tent-5 function makes worms more susceptible to bacterial infection. Importantly, we demonstrate that the function of TENT-5 in innate immunity is evolutionarily conserved, as its orthologs, TENT5A and TENT5C are induced during macrophage activation and polyadenylate mRNAs, some of which are of genes orthologous to C. elegans TENT-5 targets. In summary, our study reveals cytoplasmic polyadenylation to be a previously unknown component of the post-transcriptional regulation of innate immunity in animals.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Dominik Cysewski

LAB HEAD: Andrzej Dziembowski

PROVIDER: PXD023238 | Pride | 2022-05-31

REPOSITORIES: Pride

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TENT5 cytoplasmic non-canonical poly(A) polymerases regulate the innate immune response in animals

Project description:Innate immunity, the first line of host defense against pathogens, is tightly regulated both transcriptionally and post-transcriptionally. Through global transcriptome and proteome analyses in Caenorhabditis elegans, we uncover a modulation of the expression of secreted innate immunity effector proteins by TENT5, one of a recently described family of cytoplasmic poly(A) polymerases. Direct RNA sequencing revealed that TENT-5 polyadenylates mRNAs with signal peptide-encoding sequences, that are translated at the endoplasmic reticulum. Loss of tent-5 function makes worms more susceptible to bacterial infection. Importantly, we demonstrate that the function of TENT-5 in innate immunity is evolutionarily conserved, as its orthologs, TENT5A and TENT5C are induced during macrophage activation and polyadenylate mRNAs, some of which are of genes orthologous to C. elegans TENT-5 targets. In summary, our study reveals cytoplasmic polyadenylation to be a previously unknown component of the post-transcriptional regulation of innate immunity in animals.

2022-10-01 | GSE163549 | GEO

TENT5A mediated cytoplasmic polyadenylation in osteoblast supports proper bone formation.

Project description:The bone formation, osteogenesis, is a very complex process in which osteoblasts play a crucial role. The primary function of theses terminally differentiated mesenchymal stem cells is the secretion of fibrillary, dense, highly crosslinked type 1 collagen. Herein we show that the TENT5A gene, which mutations lead to osteogenesis imperfecta, is an active cytoplasmic poly(A) polymerase, which in osteoblast positively regulates the expression of collagen subunits and also other secreted proteins essential for proper bone formation. TENT5A substrates have shorter poly(A) tails in TENT5 KO, as revealed by direct RNA sequencing. In the case of Col1α1 and Col1α2 transcripts, the lack of cytoplasmic polyadenylation by TENT5 leads to drastic decree in the protein production but also aberrant structure. The increase in TENT5A expressing during osteoblasts differentiation positively correlates with the cytoplasmic extension of the poly(A) trials of mRNA targets. The first physiologically relevant regulation of collagen expression at the posttranscriptional level.

2022-02-16 | PXD020346 | Pride

hCAF1/CNOT7 regulates interferon signaling by targeting STAT1

Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape. mRNAs from cells expressing the siRNA siRNA duplexes targeting hCAF1, corresponding to the coding region 941-961 (kd) (hCAF1 NCBI Reference Sequence: NM_013354.5) and one non-targeting control siRNA (mock).

2013-12-31 | E-GEOD-43334 | biostudies-arrayexpress

Drosophila Trf4-1 involvement in mRNA and primary miRNA transcription

Project description:Drosophila Trf4-1 is a polyadenylation polymerase or terminal nucleotidyl transferase (PAP/TENT) that has been reported to add poly(A) tails to snRNAs in nucleus or mRNAs in cytoplasm. Here, we found that the loss of Trf4-1 resulted in the reduction of mRNAs and primary miRNAs (pri-miRNAs) in both Drosophila S2 cells and adult flies. Interestingly, the role of Trf4-1 in transcription is independent of its PAP/TENT activity. Moreover, using the chromatin immunoprecipitation assay, we uncovered that the loss of Trf4-1 led to abnormal RNA polymerase II accumulation and reduced H3K4me3 binding in promoter regions.

2019-05-01 | GSE127210 | GEO

Targeting DHX9 triggers interferon response and replication stress in Small Cell Lung Cancer [RIP-Seq II]

Project description:Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry”, has emerged as an effective strategy to convert immunologically “cold” tumors into “hot”. Through a curated CRISPR-based screen of RNA Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLCs). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other “cold” tumors where genomic instability contribute to pathology.

2024-02-01 | GSE247217 | GEO

Targeting DHX9 triggers interferon response and replication stress in Small Cell Lung Cancer [RIP-seq I]

2024-02-01 | GSE244104 | GEO

Targeting DHX9 triggers interferon response and replication stress in Small Cell Lung Cancer [RNA-seq]

2024-02-01 | GSE244103 | GEO

Identification of re-capping substrates for the cytoplasmic capping enzyme complex

Project description:The analysis of capped RNAs by massively parallel sequencing has identified a large number of previously unknown transcripts, some of which are small RNAs and others are 5M-bM-^@M-^Y truncated forms of RefSeq genes. The latter may be generated by endonuclease cleavage or by stalling of Xrn1 at defined sites. With the exception of promoter-proximal transcripts the caps on all of these are added post-transcriptionally by a cytoplasmic capping enzyme complex that includes capping enzyme and a kinase that converts 5M-bM-^@M-^Y-monophosphate ends to a diphosphate capping substrate. We previously described a modified form of capping enzyme with dominant negative activity against cytoplasmic capping (DN-cCE). A tet-inducible form of this was used to identify substrates for cytoplasmic capping by treating cytoplasmic RNA from control and induced cells with and without Xrn1. Surviving RNA was analyzed on Affymetrix Human Exon 1.0 arrays and scored for changes in probe intensity as a function of its position on each RefSeq gene to derive a factor (alpha) that could be compared between sets. Notably, transcriptome-wide changes were not evident unless RNA was treated with Xrn1. This analysis identified 2,666 uncapped mRNAs in uninduced cells, 672 mRNAs that appeared in the uncapped pool in cells expressing DN-cCE, and 835 mRNAs that were in both populations. Changes in cap status of 10 re-capping targets and 5 controls were assessed by 3 independent measures; susceptibility to Xrn1, recovery with a biotin-tagged DNA primer after ligating a complementary RNA oligonucleotide to uncapped 5M-bM-^@M-^Y ends, and binding or exclusion from a high affinity cap-binding matrix comprised of immobilized eIF4E and the corresponding binding domain of eIF4G. 3 biological replicates of 4 different samples comparing XRN1 treatment/non-treatment and Dox induction/non-induction of K294A

2012-12-20 | E-GEOD-36729 | biostudies-arrayexpress

Gene expression profiles of LPS-stimulated RAW264.7 macrophages overexpressing Tbc1d23 novel innate immune gene

Project description:We previously identified Tbc1d23 as a candidate novel regulator of innate immunity using comparative genomics RNAi screens in C. elegans and mouse macrophages. Using mice with an engineered knockout mutation in Tbc1d23 and macrophages engineered to overexpress Tbc1d23, we now show that Tbc1d23 is a general but not universal inhibitor of the innate immune response, inhibiting multiple Toll-like receptor (TLR) and Dectin signaling pathways but not NOD signaling pathways. Tbc1d23 likely acts downstream of the TLR signaling adaptors MyD88 and Trif and upstream of the transcription factor XBP1. Importantly, like XBP1, Tbc1d23 affects the maintenance but not initiation of inflammatory cytokine production induced by lipopolysaccharide (LPS). The identification of a novel temporal regulator of innate immunity signaling validates the comparative genomics approach for innate immunity gene discovery. Total of 24 samples; Tbc1d23-overexpressing line and control line; 0, 1, 3, and 5 hour LPS treatment; 3 biological replicates per group

2012-04-03 | E-GEOD-30840 | biostudies-arrayexpress

Transcripts regulated by elevated DKF-2 (WT background)

Project description:Transcriptional profiling was used to determine why DKF-2 (protein kinase D) deficiency and surfeit caused hypersensitivity and resistance, respectively, to a bacterial pathogen (P. aeruginosa 14). The studies show that DKF-2 contributes to C. elegans innate immunity by inducing expression of >75 genes that protect against pathogenic bacteria. Keywords: Induced imune response Three independent biological replicates were isolated for each strain. The strains for each replicate were grown and harvested in parallel.

2009-01-12 | E-GEOD-12456 | biostudies-arrayexpress

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