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Cell Reports Jun 2023Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell...
Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation model. Transcriptional silencing via TRIM28 maps to a 190 bp sequence encoding the intracisternal A-type particle (IAP) signal peptide, which confers retrotransposition activity. A subset of "escapee" IAPs (∼15%) exhibits significant genetic divergence from this sequence. Canonical repressed IAPs succumb to a previously undocumented demarcation by H3K9me3 and H3K27me3 in NPCs. Escapee IAPs, in contrast, evade repression in both cell types, resulting in their transcriptional derepression, particularly in NPCs. We validate the enhancer function of a 47 bp sequence within the U3 region of the long terminal repeat (LTR) and show that escapee IAPs convey an activating effect on nearby neural genes. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition.
Topics: Animals; Mice; Cell Differentiation; Embryonic Stem Cells; Endogenous Retroviruses; Histones; Tripartite Motif-Containing Protein 28; Terminal Repeat Sequences
PubMed: 37294634
DOI: 10.1016/j.celrep.2023.112625 -
International Journal of Molecular... Aug 2023Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial... (Review)
Review
Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial decidualization and spiral artery remodeling are important contributing factors in preeclampsia, a major disorder in pregnancy. Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood volume and pressure. ANP is also generated in non-cardiac tissues, such as the uterus and placenta. In recent human genome-wide association studies, multiple loci with genes involved in natriuretic peptide signaling are associated with gestational hypertension and preeclampsia. In cellular experiments and mouse models, uterine ANP has been shown to stimulate endometrial decidualization, increase TNF-related apoptosis-inducing ligand expression and secretion, and enhance apoptosis in arterial smooth muscle cells and endothelial cells. In placental trophoblasts, ANP stimulates adenosine 5'-monophosphate-activated protein kinase and the mammalian target of rapamycin complex 1 signaling, leading to autophagy inhibition and protein kinase N3 upregulation, thereby increasing trophoblast invasiveness. ANP deficiency impairs endometrial decidualization and spiral artery remodeling, causing a preeclampsia-like phenotype in mice. These findings indicate the importance of natriuretic peptide signaling in pregnancy. This review discusses the role of ANP in uterine biology and potential implications of impaired ANP signaling in preeclampsia.
Topics: Humans; Animals; Signal Transduction; Natriuretic Peptides; Pre-Eclampsia; Uterus; Hypertension, Pregnancy-Induced; Placenta; Serine Endopeptidases
PubMed: 37569683
DOI: 10.3390/ijms241512309 -
Cell Reports Jun 2023Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation...
Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.
Topics: Tyrosine-tRNA Ligase; Protein Transport; Phosphorylation; Nuclear Localization Signals; Oxidative Stress
PubMed: 37314928
DOI: 10.1016/j.celrep.2023.112632 -
Applied Microbiology and Biotechnology Aug 2023Filamentous fungi are able to produce a wide range of valuable proteins and enzymes for many industrial applications. Recent advances in fungal genomics and experimental... (Review)
Review
Filamentous fungi are able to produce a wide range of valuable proteins and enzymes for many industrial applications. Recent advances in fungal genomics and experimental technologies are rapidly changing the approaches for the development and use of filamentous fungi as hosts for the production of both homologous and heterologous proteins. In this review, we highlight the benefits and challenges of using filamentous fungi for the production of heterologous proteins. We review various techniques commonly employed to improve the heterologous protein production in filamentous fungi, such as strong and inducible promoters, codon optimization, more efficient signal peptides for secretion, carrier proteins, engineering of glycosylation sites, regulation of the unfolded protein response and endoplasmic reticulum associated protein degradation, optimization of the intracellular transport process, regulation of unconventional protein secretion, and construction of protease-deficient strains. KEY POINTS: • This review updates the knowledge on heterologous protein production in filamentous fungi. • Several fungal cell factories and potential candidates are discussed. • Insights into improving heterologous gene expression are given.
Topics: Fungi; Protein Transport; Carrier Proteins; Protein Sorting Signals; Codon
PubMed: 37405433
DOI: 10.1007/s00253-023-12660-8 -
ELife Jun 2024Modification of pectin, a component of the plant cell wall, is required to facilitate signaling by a RALF peptide, which is essential for many physiological and...
Modification of pectin, a component of the plant cell wall, is required to facilitate signaling by a RALF peptide, which is essential for many physiological and developmental processes.
Topics: Signal Transduction; Pectins; Cell Wall; Arabidopsis; Arabidopsis Proteins
PubMed: 38832933
DOI: 10.7554/eLife.99053 -
Journal of Virology Oct 2023African swine fever virus (ASFV) is the cause of the current major animal epidemic worldwide. This disease affects domestic pigs and wild boars, has spread since 2007...
African swine fever virus (ASFV) is the cause of the current major animal epidemic worldwide. This disease affects domestic pigs and wild boars, has spread since 2007 through Russia, Eastern Europe, and more recently to Western European countries, and since 2018 emerged in China, from where it spread throughout Southeast Asia. Recently, outbreaks have appeared in the Caribbean, threatening the Americas. It is estimated that more than 900,000 animals have died directly or indirectly from ASFV since 2021 alone. One of the features of ASFV infection is hemoadsorption (HAD), which has been linked to virulence, although the molecular and pathological basis of this hypothesis remains largely unknown. In this study, we have analyzed and identified the key players responsible of HAD, contributing to the identification of new determinants of ASFV virulence, the understanding of ASFV pathogenesis, and the rational development of new vaccines.
Topics: Animals; African Swine Fever; African Swine Fever Virus; Glycosylation; Hemadsorption; Protein Sorting Signals; Swine; Virulence; Viral Proteins
PubMed: 37768082
DOI: 10.1128/jvi.01030-23 -
Molecular and Cellular Endocrinology May 2024Insulin-like peptides are a group of hormones crucial for regulating metabolism, growth, and development in animals. Invertebrates, such as C. elegans, have been... (Review)
Review
Insulin-like peptides are a group of hormones crucial for regulating metabolism, growth, and development in animals. Invertebrates, such as C. elegans, have been instrumental in understanding the molecular mechanisms of insulin-like peptides. Here, we review the 40 insulin-like peptide genes encoded in the C. elegans genome. Despite the large number, there is only one C. elegans insulin-like peptide receptor, called DAF-2. The insulin and insulin-like growth factor signaling (IIS) pathway is evolutionarily conserved from worms to humans. Thus C. elegans provides an excellent model to understand how these insulin-like peptides function. C. elegans is unique in that it possesses insulin-like peptides that have antagonistic properties, unlike all human insulin-like peptides, which are agonists. This review provides an overview of the current literature on C. elegans insulin-like peptide structures, processing, tissue localization, and regulation. We will also provide examples of insulin-like peptide signaling in C. elegans during growth, development, germline development, learning/memory, and longevity.
Topics: Animals; Humans; Caenorhabditis elegans; Insulin-Like Peptides; Insulin; Somatomedins; Signal Transduction; Caenorhabditis elegans Proteins; Longevity; Forkhead Transcription Factors
PubMed: 38346555
DOI: 10.1016/j.mce.2024.112173 -
Cancer Letters Aug 2023Chimeric antigen receptor T cell immunotherapy has achieved promising therapeutic effects in the treatment of hematological malignancies. However, there are still many...
Chimeric antigen receptor T cell immunotherapy has achieved promising therapeutic effects in the treatment of hematological malignancies. However, there are still many obstacles, including on-target off-tumor antigen expression, that prevent successful application to solid tumors. We designed a tumor microenvironment (TME) regulated system chimeric antigen receptor T (MRS.CAR-T) which can only be auto-activated in the solid TME. B7-H3 was selected as the target antigen for esophageal carcinoma. An element comprising a human serum albumin (HSA) binding peptide and a matrix metalloproteases (MMPs) cleavage site was inserted between the 5' terminal signal peptide and single chain fragment variable (scFv) of the CAR skeleton. Upon administration, HSA bound the binding peptide in MRS.B7-H3.CAR-T effectively and promoted proliferation and differentiation into memory cells. MRS.B7-H3.CAR-T was not cytotoxic in normal tissues expressing B7-H3 as the antigen recognition site in the scFv was cloaked by HSA. The anti-tumor function of MRS.B7-H3.CAR-T was recovered once the cleavage site was cleaved by MMPs in the TME. The anti-tumor efficacy associated with MRS.B7-H3.CAR-T cells was improved compared to classic B7-H3.CAR-T cells in vitro and less IFN-γ was released, suggesting a treatment that may induce less extent of cytokine release syndrome-mediated toxicity. In vivo, MRS.B7-H3.CAR-T cells had strong anti-tumor activity and were safe. MRS.CAR-T represents a novel strategy to improve the efficacy and safety of CAR-T therapy in solid tumors.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Esophageal Squamous Cell Carcinoma; Antigens, Neoplasm; Esophageal Neoplasms; Tumor Microenvironment
PubMed: 37422126
DOI: 10.1016/j.canlet.2023.216303 -
Nature Communications Nov 2023Quorum sensing (QS) is a crucial regulatory mechanism controlling bacterial signalling and holds promise for novel therapies against antimicrobial resistance. In...
Quorum sensing (QS) is a crucial regulatory mechanism controlling bacterial signalling and holds promise for novel therapies against antimicrobial resistance. In Gram-positive bacteria, such as Streptococcus pneumoniae, ComA is a conserved efflux pump responsible for the maturation and secretion of peptide signals, including the competence-stimulating peptide (CSP), yet its structure and function remain unclear. Here, we functionally characterize ComA as an ABC transporter with high ATP affinity and determined its cryo-EM structures in the presence or absence of CSP or nucleotides. Our findings reveal a network of strong electrostatic interactions unique to ComA at the intracellular gate, a putative binding pocket for two CSP molecules, and negatively charged residues facilitating CSP translocation. Mutations of these residues affect ComA's peptidase activity in-vitro and prevent CSP export in-vivo. We demonstrate that ATP-Mg triggers the outward-facing conformation of ComA for CSP release, rather than ATP alone. Our study provides molecular insights into the QS signal peptide secretion, highlighting potential targets for QS-targeting drugs.
Topics: Quorum Sensing; Bacterial Proteins; Peptides; Streptococcus pneumoniae; Adenosine Triphosphate
PubMed: 37935699
DOI: 10.1038/s41467-023-42852-9