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6 recordsLinked to original sources
PubMed2026

PTBP1 at the host-virus interface: mechanistic roles in viral RNA translation, replication, and immune modulation.

Viruses require the involvement of host RNA binding proteins for completion of important steps of their life cycle. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein found ubiquitously which performs important regulatory functions like alternative splicing, RNA stability, RNA localization, and translation by virtue of its four RRMs and shuttling between nucleus and cytoplasm. There is increasing evidence showing that many viruses make use of such regulatory roles of PTBP1 to facilitate their gene expression and replication. This review describes the existing mechanistic knowledge about the PTBP1 functions during viral infection, paying attention to the role of PTBP1 in viral RNA translation, viral RNA genome replication, and regulation of host antiviral response. Special attention is paid to the regulation by PTBP1 of IRES-dependent translation of enteroviruses and hepatitis C virus, as well as to the PTBP1 contribution to RNA stabilization, long-distance RNA interactions, and genome cyclization of flaviviruses such as dengue virus and Japanese encephalitis virus. Recent data on the PTBP1 function in coronavirus RNA metabolism are discussed as well. Furthermore, the role of PTBP1 in being both proviral and antiviral is reviewed in terms of innate immunity signalling pathways, stress granule biology, and virus-host interaction. Finally, we will explore the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein.

Polypyrimidine Tract-Binding Protein↗
PubMed1978

A restriction endonuclease cleavage map of mitochondrial DNA from transformed hamster cells.

Mitochondrial DNA from cultured C13/B4 hamster cells was cleaved by the restriction endonucleases Hpa II, Hind III, Eco RI and Bam HI into 7, 5, 3 and 2 unique fragments, respectively. The summed molecular weights of fragments obtained from electrophoretic mobilities in agarose-ethidium bromide gels (with Hpa I-cleaved T7 DNA as standard) and electron microscopic analysis of fragment classes isolated from gels (with SV40 DNA as standard) were in good agreement with the size of 10.37 +/- 0.22 x 10(6) daltons (15,700 +/- 330 nucleotide pairs) determined for the intact circular mitochondrial genome. Cyclization of all Hind III, Eco RI and Bam HI fragments was observed. A cleavage map containing the 17 restriction sites (+/- 1% s.d.) was constructed by electrophoretic analysis of 32P-labeled single- and double-enzyme digestion products and reciprocal redigestion of isolated fragments. The 7 Hpa II sites were located in one half of the genome. The total distribution of the 17 cleavages around the genome was relatively uniform. The position of the D-loop was determined from its location and expansion on 3 overlapping restriction fragments.

Animals↗
PubMed2026

Systematic Genome Mining of Peptide Metallophore Pathways Uncovers Novel Dibenzo-α-Pyrone Siderophores in Streptomyces sp. HB-R818.

Metallophores are metal-chelating natural products that enable microorganisms to acquire essential metal ions and mediate processes such as iron uptake, quorum sensing, and interspecies competition. Metallophores also display potent antimicrobial and anticancer activities, highlighting their biomedical and biotechnological potential. Despite Streptomyces being prolific producers of bioactive metabolites, their metallophore pathways remain largely unexplored. Here, we systematically mined 519 reference Streptomyces genomes to elucidate the distribution, diversity, and structural features of metallophores and identified a new metallophore biosynthetic gene cluster (BGC) (ser) from sponge-derived Streptomyces sp. HB-R818. Using a metabologenomics-based strategy, five new siderophore analogs serobactins A-E (1-5) and known enterobactin (6) were isolated. These compounds show potential to inhibit tumor invasion and feature a unique dibenzo-α-pyrone scaffold in structure, formed through the cyclization of an extra 2,3-dihydroxybenzoic acid with 2,3-dihydroxybenzoyl serine. The BGC (ser) was validated by the nonribosomal peptide synthetase gene knockout; the biosynthesis of 1-6 was proposed.

Siderophores↗
PubMed2026

CircRNA-based CD19-targeted CAR-NK therapy for B-cell acute lymphoblastic Leukemia using a Coccidioides immitis-derived group II intron platform.

Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has demonstrated notable clinical efficacy in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but its wider clinical applicability is constrained by long manufacturing processes, substantial costs, and severe adverse events. A potentially safer and more accessible alternative is provided by CAR-Natural killer (CAR-NK) cell therapy. Currently, most CAR-NK cells are generated using viral transduction, which is labor-intensive and associated with risks of genomic integration. Electroporation of CAR-encoding mRNA provides a non-integrating alternative but results in only transient CAR expression. Circular RNA (circRNA), owing to its enhanced stability and prolonged protein expression capacity, has recently emerged as a promising alternative to linear mRNA. To overcome the limitations of transient mRNA expression, we generated circRNA using a Group II intron-mediated cyclization system incorporating a newly selected Coccidioides immitis-derived Group II intron. The newly established Coccidioides immitis-derived Group II intron circularization system efficiently generated circRNA and supported more durable EGFP expression than linear mRNA in both HEK293T and NK92 cells. Using this system, we successfully developed a circRNA-based CD19-targeted CAR-NK platform. CircRNA-engineered CD19-targeted CAR-NK92 cells maintained more durable CAR expression and showed stronger antitumor activity at later time points. In mouse models of B-ALL, circRNA-engineered CAR-NK92 cells demonstrated better tumor control and extended survival compared with their linear mRNA-engineered counterparts. These results support the potential of circRNA-based CAR-NK therapy as an effective approach for enhancing the safety and efficacy of cancer immunotherapy.

Humans↗
PubMed2025

RRNPP quorum-sensing repertoires in the salivarius group genomes: overrepresentation and synchronous activation of SHP/Rgg systems in Streptococcus thermophilus.

UNLABELLED: In Bacillota, quorum sensing can be mediated by RRNPP regulators that are activated by autoinducing peptides (AIPs). In this study, we derived a hidden Markov model profile from a 3D-informed alignment to establish RRNPP repertoires for 527 genomes of streptococci in the salivarius group and identified probable AIPs. The salivarius group encompasses Streptococcus salivarius and Streptococcus vestibularis, which are part of the normal human oral microflora, and Streptococcus thermophilus, one of the most widely used bacteria in the dairy industry. We observed a large amount of plasticity in these repertoires, as well as profound differences among species. Notably, S. salivarius displayed an accumulation of ComR regulators, while S. thermophilus displayed an accumulation of Rgg regulators. The latter family included SHP-associated Rgg regulators, systems in which SHPs serve as AIPs; most of these regulators control the production of post-translationally modified peptides (RaS-RiPPs). Their level of richness contrasts with the genome reduction that accompanied S. thermophilus' adaptation to milk. We then used liquid chromatography-high resolution tandem mass spectrometry to analyze the activity of the eight most common SHP/Rgg systems by characterizing the SHPs and RaS-RiPPs found in the supernatants. We detected four SHPs and one RaS-RiPP that have never been seen before in S. thermophilus, and we showed that seven of the eight SHP/Rgg systems were functional. Finally, by simultaneously monitoring the amounts of both the SHPs and RaS-RiPPs, we demonstrated that the fates of these two peptide types differed during growth. SHP presence in the supernatant was transient, a pattern likely related to the peptides' signaling role. IMPORTANCE: Streptococcus thermophilus possesses an unusually high number of Rgg regulators, which are activated by SHP pheromones that control the production of RaS-RiPPs, peptides with cyclization motifs and growth inhibition properties. We conducted an in silico analysis of regulator repertoires across a wide range of strains; a subsequent experimental study revealed that the majority of the SHP/Rgg systems were functional. Employing an optimized liquid chromatography-high resolution tandem mass spectrometry protocol, we were able to better detect and follow SHP and RaS-RiPP accumulation. While RaS-RiPPs accumulated during growth, SHPs were only transiently present in the extracellular environment. This observation suggests that we could manipulate quorum sensing by adding SHPs to the growth medium and highlights the need to study the functions of the RaS-RiPPs.

Streptococcus thermophilus↗
PubMed2025

Enzymatic Anti-Baldwin Ring-Closure Cascade for Fused Bicyclic Ether Formation.

Pyrenulic acids are cytotoxic polyketides isolated from the ascomycete Pyrenula sp. derived from Vietnamese lichen that are characterized by complex fused cyclic core structures. Genome sequencing, in silico sequence analysis, and RT-PCR studies identified the pyrenulic acid (pya) biosynthetic gene cluster. Based on a functional analysis of the enzymes by expression of each gene in a heterologous host using Aspergillus nidulans, we discovered two cytochrome P450s PyaJ and PyaG that effect epoxidation and hydroxylation of the alkyl chain terminal, respectively, and an α/β hydrolase PyaF that constructs a 6- and 7-membered fused bicyclic diether skeleton by catalyzing successive epoxide ring-opening 6-endo and 7-endo cyclization reactions. To elucidate the detailed mechanism of pyrenulic acid formation, we obtained PyaF as a recombinant enzyme and performed an in vitro experiment, which confirmed catalysis by PyaF of the cyclization reaction. In addition, we performed alignment analysis of PyaF with α/β hydrolases with known functions, as well as an in-depth computational study. In-depth computational analyses of the cyclization reaction pathways with density functional theory quantum mechanics and detailed characterization of PyaF by Chai-1-based protein structure modeling with molecular dynamics simulations and site-specific mutagenesis predicted the active amino acid residues of this serine α/β hydrolase to be an unusual catalytic serine tetrad involving Ser170, Asn342, Asp314, and His169, with Tyr255 and His284 acting as general bases to facilitate opening of the epoxides. Our study provides insight into how regioselectivity of enzymatic anti-Baldwin epoxide ring-opening cascades for the formation of a fused cyclic ether structure is controlled.

Cyclization↗