STAT3β is a tumor suppressor in acute myeloid leukemia

Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains elusive. Therefore, we analyzed the STAT3β/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3β/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in AML, we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9-dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3β depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3β plays an essential tumor-suppressive role in AML

Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion

© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Approximately 90% of these 385 genes are conserved in humans, and one-third of the conserved genes have been implicated in human disease. Furthermore, many have roles in developmental processes, which suggests that mitochondrial function and their response to stress are defined during development and maintained throughout life. Our dataset primarily contains mitochondrial enhancers and non-mitochondrial suppressors of UPRmt, indicating that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function, which, when disrupted, can be compensated for by many different cellular processes. Analysis of the subsets “non-mitochondrial enhancers” and “mitochondrial suppressors” suggests that organellar contact sites, especially between the ER and mitochondria, are of importance for mitochondrial homeostasis. In addition, we identified several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants and found a potential link between pre-mRNA splicing and UPRmt activation.11Nsciescopu

A transcriptomics resource reveals a transcriptional transition during ordered sarcomere morphogenesis in flight muscle

Muscles organise pseudo-crystalline arrays of actin, myosin and titin filaments to build force-producing sarcomeres. To study sarcomerogenesis, we have generated a transcriptomics resource of developing flight muscles and identified 40 distinct expression profile clusters. Strikingly, most sarcomeric components group in two clusters, which are strongly induced after all myofibrils have been assembled, indicating a transcriptional transition during myofibrillogenesis. Following myofibril assembly, many short sarcomeres are added to each myofibril. Subsequently, all sarcomeres mature, reaching 1.5 µm diameter and 3.2 µm length and acquiring stretch-sensitivity. The efficient induction of the transcriptional transition during myofibrillogenesis, including the transcriptional boost of sarcomeric components, requires in part the transcriptional regulator Spalt major. As a consequence of Spalt knock-down, sarcomere maturation is defective and fibers fail to gain stretch-sensitivity. Together, this defines an ordered sarcomere morphogenesis process under precise transcriptional control - a concept that may also apply to vertebrate muscle or heart development

Compromised Mitochondrial Protein Import Acts as a Signal for UPRmt

International audienceThe induction of the mitochondrial unfolded protein response (UPRmt) results in increased transcription of the gene encoding the mitochondrial chaperoneHSP70. We systematically screened the C.elegans genome and identified 171 genes that, whenknocked down, induce the expression of anhsp-6HSP70 reporter and encode mitochondrial proteins.These genes represent many, but not all, mitochondrial processes (e.g., mitochondrial calcium homeostasis and mitophagy are not represented).Knockdown of these genes leads to reduced mitochondrial membrane potential and, hence,decreased protein import into mitochondria. Inaddition, it induces UPR mtin a manner that is dependent on ATFS-1 but that is not antagonized by the kinase GCN-2. We propose that compromised mitochondrial protein import signals the induction of UPR mt and that the mitochondrial targeting sequence of ATFS-1 functions as a sensor for this signal

Additional file 1: of The complete and fully assembled genome sequence of Aeromonas salmonicida subsp. pectinolytica and its comparative analysis with other Aeromonas species: investigation of the mobilome in environmental and pathogenic strains

Figure S1. Sequencing and assembly strategy of the A. salmonicida subsp. pectinolytica strain 34mel genome. Figure S2. Gene similarity and Mummer alignments to other Aeromonas genomes. Figure S3. Transposon conglomerates from A. salmonicida subsp. pectinolytica strain 34mel. Figure S4. Transposon family content in analyzed Aeromonas strains. Figure S5. Comparison of the A. salmonicida subsp. pectinolytica strain 34mel genome, plasmid pFBAOT6 from Aeromonas caviae, and transposon Tn1721. Table S1. Pathogenic as well as temperature-dependent growth features of analyzed Aeromonas strains. Table S2. General genome features of A. salmonicida subsp. pectinolytica strain 34mel. Table S3. Polymorphic sites in rRNAs from A. salmonicida subsp. pectinolytica strain 34mel. Table S4. Genes disrupted by transposons in A. salmonicida subsp. pectinolytica strain 34mel. Table S5. Transposon details from analyzed Aeromonas strains. Table S6. Genes retained in transposon TnAs1 from the environmental IncP-9 TOL plasmid pWW0 from Pseudomonas putida. Text S1. Annotation details for RNA genes in the A. salmonicida subsp. pectinolytica strain 34mel genome. Text S2. Short unassigned contigs from the A. salmonicida subsp. pectinolytica strain 34mel draft genome. Text S3. Transposons: nomenclature and completeness. Text S4. On transposon counting and the meaning of “ISAs11”. Text S5. Insertions on pFBAOT6 in transposon Tn1721 and details of the regions shared with the A. salmonicida subsp. pectinolytica strain 34mel genome. Text S6. Details of PacBio library preparation, sequencing, and assembly of the genome from A. salmonicida subsp. pectinolytica strain 34mel. (PDF 1171 kb

The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury.

International audienceAlthough AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance

Mitochondrial fusion is required for regulation of mitochondrial DNA replication.

Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number. To decipher the link between mitochondrial dynamics and mtDNA maintenance, we studied mouse embryonic fibroblasts (MEFs) and mouse cardiomyocytes with disruption of mitochondrial fusion. Super-resolution microscopy revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to nucleoid clustering. Remarkably, fluorescence in situ hybridization (FISH), bromouridine labeling in MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. Furthermore, the profound mtDNA depletion in mouse hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but instead we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA

Vav proteins are key regulators of card9 signaling for innate antifungal immunity

Fungal infections are major causes of morbidity and mortality, especially in immunocompromised individuals. The innate immune system senses fungal pathogens through Syk-coupled C-type lectin receptors (CLRs), which signal through the conserved immune adaptor Card9. Although Card9 is essential for antifungal defense, the mechanisms that couple CLR-proximal events to Card9 control are not well defined. Here, we identify Vav proteins as key activators of the Card9 pathway. Vav1, Vav2, and Vav3 cooperate downstream of Dectin-1, Dectin-2, and Mincle to engage Card9 for NF-κB control and proinflammatory gene transcription. Although Vav family members show functional redundancy, Vav1/2/3 mice phenocopy Card9 animals with extreme susceptibility to fungi. In this context, Vav3 is the single most important Vav in mice, and a polymorphism in human VAV3 is associated with susceptibility to candidemia in patients. Our results reveal a molecular mechanism for CLR-mediated Card9 regulation that controls innate immunity to fungal infections.This work was supported by research grants from the Helmholtz Alliance Preclinical Comprehensive Cancer Center, the DFG (SFB 1054 and RU 695/6-1), and an ERC Advanced Grant (FP7, grant agreement 322865) (to J.R.). The work of X.R.B. has been supported by grants from the Spanish Ministry of Economy and Competitiveness (RD12/0036/0002 and SAF2015-64556-R), Worldwide Cancer Research (14-1248), and the Ramón Areces Foundation. M.G.N. was supported by an ERC Consolidator Grant (310372). V.L.T. was supported by the Francis Crick Institute which receives its core funding from the MRC (FC001194), Cancer Research UK (FC001194) and the Wellcome Trust (FC001194).Peer Reviewe