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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]

ABSTRACT: RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. We performed targeted RBP CRISPR/Cas9 screening and identified density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibited reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppressed tumor growth and enhanced the tumor-killing activity of CD8+ T cells. Mechanistically, DENR antagonized the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (JAK2); thus, DENR deficiency impaired JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discovered that the RBP DENR is a novel regulator in PD-L1 expression and highlighted the potential of DENR as a therapeutic target for immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE184048 | GEO | 2022/02/28

REPOSITORIES: GEO

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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Project description:To identify the potential signaling pathway involved in DENR KO cells upon PD-L1 production, we harvested IFNγ-treated control and DENR KO cells for RNA-seq. Bioinformatic analysis of the RNA-seq data showed that 114 genes, including PD-L1, were significantly downregulated in DENR KO cells, and multiple classical signaling pathways, including JAK-STAT, and PD-L1, were enriched.

2022-02-28 | GSE183980 | GEO

DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Project description:DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]

Project description:DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]

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Master stress response gene ATF4 & other oncogenes are translated by DENR-dependent reinitiation

Project description:Translation efficiency varies 1000-fold between different mRNAs, thereby strongly impacting protein expression. Translation of the master stress response gene ATF4 increases in response to stress, but the molecular mechanisms are not well understood. We discover here that translation initiation factors DENR, MCTS1 and eIF2D are absolutely required to induce ATF4 translation upon stress, by promoting translation reinitiation on the ATF4 5’UTR. Hence DENR and MCTS1 are important players in the cellular Integrated Stress Response. We find DENR and MCTS1 promote reinitiation after long uORFs with specific penultimate codons, due to the tRNA that remains attached to 40S ribosomes after translation termination. This provides a model for how DENR and MCTS1 promote translation reinitiation. Since cancer cells are exposed to many stresses, they require ATF4 for survival and proliferation. We find a strong correlation between DENR•MCTS1 expression and ATF4 activity across cancers. Additional oncogenes including a-Raf, c-Raf and Cdk4 have long uORFs and are translated in a DENR•MCTS1 dependent manner. This explains in part why DENR and MCTS1 are oncogenes.

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Identification of DENR-interacting proteins in NIH3t3 cells using a co-IP MS-MS approach on endogenously tagged DENR.

Project description:Among the transcript features that regulate translation rate, upstream open reading frames (uORFs) have emerged as a major class of inhibitory elements which limit how many scanning ribosomes reach the start codon of the main protein coding sequence (CDS). Two processes are implicated in ensuring that CDS translation of uORF-containing transcripts can take place nevertheless: first, leaky-scanning, which involves the bypassing of uORF start codons by the scanning 40S ribosome, and second, re-initiation (REI), which allows the 40S subunit of the ribosome that terminated on the uORF stop codon to resume scanning to reach a downstream start codon. REI has remained particularly enigmatic, as it is at odds with generally accepted principles of conventional translation initiation, termination and post-termination subunit recycling. The heterodimer MCTS1-DENR is the first re-initiation-specific factor that has been identified. MCTS1 has been described as the only obligatory partner of DENR. Nevertheless, MCTS1 depletion phenotypes do not always copy the phenotype of DENR depletion in mammalian cells, suggesting that another partner could compensate for the lack of MCTS1. We performed co-immunoprecipitation followed by MS-MS analysis of endogenously FLAG-tagged DENR and identified MCTS2 as a new protein partner. MCTS2 is a homolog and retrogene copy of MCTS1. Downstream analyses demonstrated that MCTS2-DENR was able to promote re-initiation in vitro and showed that Mcts2 mRNA was highly abundant and the protein at least as efficiently synthesized as MCTS1 in NIH3t3 cells, implying that MCTS2 might be the main expressed variant in certain cell types.

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Polysomes from DENR knockdown cells

Project description:The aim was to identify transcripts that are poorly translated upon knockdown of DENR. Lysates from control (GFP) and DENR knockdown S2 cells were run on polysome gradients. RNA from the (80S peak + polysome peaks) was isolated and analyzed by microarrays. In parallel, total RNA from the cells was also profiled as a normalization control and profiled. The 'translation score' of translated mRNA to total RNA was then calculated for control and DENR knockdown cells. Two biological replicates for DENR knockdown and GFP knockdown were performed. For each sample, (80S+polysomes) and total RNA were profiled, leading to 8 samples in total.

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Analysis of mouse T cell transcription profile after co-culture with BaF3 cells with or without the oncogenic point mutation JAK2 V617F

Project description:The activation of PD-1 (Programmed Death receptor-1) on T cells can cause T cell exhaustion and immune tolerance. Some tumors up-regulate the expression of the ligand of PD-1, namely PD-L1 (Programmed Death Receptor-Ligand 1), thus preventing anti-tumor immune response and promoting immune-escape. Previous studies have shown that JAK2 (Janus Kinase 2) signaling can promote PD-L1 expression in Hodgkin Lymphoma. In Myeloproliferative Neoplasms (MPN), JAK2 is frequently characterized by the the presence of the point-mutation V617F, which leads to its constitutive activation and to uncontrolled cell proliferation and survival. Accordingly, tumor cell lines expressing JAK2 V617F express higher levels of PD-L1 as compared to tumor cell lines negative for such mutations. In this experiment, we transfected BaF3 cells with a vector (plasmid for Murine Stem Cell Virus) containing the gene for JAK2 with the point-mutation V617F. As control, we used BaF3 cells transfected with the same vector, but without the gene for JAK2 V617F (empty vector). Both the cell lines (with/without JAK2 V617F) were co-cultured with primary murine T cells. When co-cultured with BaF3 cells expressing JAK2 V617F, T cells upregulated genes connected to senescence pathways, showed increased apoptosis, less cytokine production, and displayed other forms of dysfunction which can be associated with the activation of PD-1.

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Ribosome profiling analysis of Denr and Eif2d depleted cells reveals the absence of re-initiation function of EIF2D

Project description:Among the transcript features that regulate translation rate, upstream open reading frames (uORFs) have emerged as a major class of inhibitory elements which limit how many scanning ribosomes reach the start codon of the main protein coding sequence (CDS). Two processes are implicated in ensuring that CDS translation of uORF-containing transcripts can take place nevertheless: first, leaky-scanning, which involves the bypassing of uORF start codons by the scanning 40S ribosome, and second, re-initiation (REI), which allows the 40S subunit of the ribosome that terminated on the uORF stop codon to resume scanning to reach a downstream start codon. REI has remained particularly enigmatic, as it is at odds with generally accepted principles of conventional translation initiation, termination and post-termination subunit recycling. MCTS1-DENR is the first re-initiation-specific factor that has been identified. Its homolog, EIF2D, is assumed to act in uORF REI as well, yet formal proof of EIF2D-mediated REI has remained scarce. In our study, we present our in vivo analyses of DENR and EIF2D in translation re-initiation in mammalian cells. At the transcriptome-wide scale, ribosome profiling clearly identifies DENR-dependent REI, yet disproves the assumption that EIF2D also functions as a REI-factor.

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