Biology Direct最新文献

Background: The early evolution of animals is characterized by the emergence of complex tissues, organs, and integument, made possible in part by the diversification of groups of structural proteins. The abundance of this new kind of organic material in the environment would have provided novel nutrient opportunities for microbes, as part of the beginnings of animal-microbial coevolution. Indeed, a diverse ensemble of extant microbial groups appear to possess the enzymatic ability to cleave collagen, the most abundant animal-specific protein, through the use of matrix metalloproteinases (MMPs). In animals, MMPs serve to reshape the extracellular matrix in the course of development, but their prevalence in the microbial world has been largely overlooked.

Results: MMPs have extensive diversity in Bacteria, Eumetazoa, and Streptophyta. We show that in marine metagenomes, MMP abundance is highly correlated with chitinase abundance, implying that even microbial MMPs are associated with animal-derived substrates. Reconstructing the phylogeny of MMP proteins reveals a history of rapid diversification, as well as multiple interkingdom and interdomain horizontal gene transfers. Included among these is a transfer to the ancestral lineage of the archaeal family Methanosarcinaceae, constraining this group to postdate the evolution of collagen, and therefore animal diversification.

Conclusions: MMPs have an unusual genetic history, marked by multiple instances of gene transfer between bacteria and multicellular eukaryotes, a smoking gun for some of the earliest coevolution between prokaryotes and metazoans. By calculating an end-Permian divergence of Methanosarcina, we demonstrate that the phylogenies of substrate-specific enzymes can provide valuable older-bound age calibrations for improving molecular clock age estimates across the Tree of Life.

Background: SARS-CoV-2 papain-like protease (PLpro) is essential for viral replication and immune evasion. It contains an N-terminal ubiquitin-like (Ubl) domain, whose involvement in enzymatic function remains poorly understood.

Results: In this study, we investigated the role of the Ubl domain in modulating the structural dynamics and catalytic efficiency of PLpro. Using molecular dynamics (MD) simulations, inhibitor binding assays, and steady-state kinetic analyses, we found that the Ubl domain stabilizes critical structural elements, notably the ridge helix in the thumb subdomain. Removal of the Ubl domain altered substrate processing, reducing catalytic efficiency of the enzyme. Interestingly, free ubiquitin enhanced enzymatic activity, likely via non-canonical binding sites distinct from the SUb1 and SUb2 sites.

Conclusion: These findings uncover a regulatory role for the Ubl domain in allosteric modulation of PLpro activity and reveal additional layers of enzymatic plasticity. Understanding these mechanisms could guide the design of future antiviral therapeutics targeting PLpro's regulatory or allosteric sites.

Background: Advancements in precision oncology have generated increased interest in the prognostic and therapeutic capabilities of transcription factors, among which HMGA1 is significantly correlated with LUAD prognosis. However, our understanding of HMGA1 remains insufficient. This study seeks to elucidate the biological functions of HMGA1 and to investigate the underlying mechanisms.

Methods: The prognostic value of HMGA1 was validated across multiple independent patient cohorts with LUAD, and its impact on tumor proliferation was verified by both in vitro and in vivo models. A series of experiments were performed to investigate the underlying molecular mechanism, including RNA sequencing, co-immunoprecipitation and chromatin immunoprecipitation.

Results: HMGA1 plays a crucial role in promoting the proliferation of LUAD. The underlying mechanism involves the recruitment of STAT1 to the promoter region of DDAH1, which synergistically increases its transcription and subsequently activates the ADMA/NO signaling pathway. Notably, the STAT1 inhibitor fludarabine has been shown to effectively impede the progression of LUAD models characterized by high levels of HMGA1.

Conclusion: Our research reveals a previously unrecognized mechanism through which the HMGA1/STAT1 complex facilitates LUAD proliferation by transcriptionally activating DDAH1. Moreover, we propose that fludarabine could serve as a promising therapeutic option for LUAD patients exhibiting elevated levels of HMGA1.

Background: Hepatocellular carcinoma (HCC) is significantly influenced by hepatitis B virus (HBV) infection. However, the roles of ferroptosis and ubiquitination modifications in this context remain poorly understood.

Methods: In this study, we utilized immunoprecipitation, immunofluorescence, and analysis of ubiquitin modifications to explore the regulatory mechanisms of MINPP1 in ferroptosis and its effects on tumor progression. Further mechanistic studies revealed that ZRANB1 regulates the K33-linked ubiquitination of CTSB. Ultimately, the contribution of the MINPP1-CTSB axis to tumor progression was validated using in vivo experiments.

Results: Our study demonstrates that MINPP1 regulates ferroptosis in HBV-positive HCC cells via a glycolytic bypass mechanism. Bioinformatics analysis indicates that MINPP1 stabilizes CTSB, thereby participating in the regulation of ferroptosis. Specifically, MINPP1 modulates K33-linked deubiquitination of CTSB through ZRANB1, which stabilizes CTSB expression and identifies its deubiquitination site. In contrast, the MINPP1-ZRANB1-CTSB axis does not regulate ferroptosis in HBV-negative HCC cells. However, upon the introduction of HBV into these cells, the MINPP1-ZRANB1-CTSB axis becomes active and promotes ferroptosis. Finally, in vivo assays showed that MINPP1 regulates tumor progression by regulating K33-linked ubiquitination of CTSB, thereby affecting ferroptosis levels.

Conclusion: Our research showed outcomes suggest that the MINPP1-ZRANB1-CTSB axis promotes ferroptosis in HBV-positive HCC cells through glycolysis, emphasizing the function of MINPP1 in mediating ferroptosis in HBV-related HCC cells via CTSB deubiquitination modification. This provides valuable insights and a foundation for the treatment of HBV-associated HCC.

Pseudomonas aeruginosa, one of the most prevalent pathogens, is notorious for its multidrug resistance, necessitating novel therapeutic strategies. Phage therapy has emerged as a promising alternative treatment strategy, which offers a dual advantage by directly killing bacteria and modulating host-pathogen interactions. Here, we identify PavP (PaoP5_160), a small protein encoded by bacteriophage PaoP5, which exhibits bacteriostatic activity on P. aeruginosa while altering virulence pathways at sub-inhibitory concentrations. Specifically, PavP impairs bacterial motility, enhances biofilm formation, and upregulates type 3 secretion system expression. The global transcriptome analysis shows that PavP modulates multiple pathways which participate in the pathogenicity and cell vitality of host bacteria. Crucially, in vivo virulence assays confirm that PavP attenuates P. aeruginosa pathogenicity. Our results reveal PavP as a multifunctional virulence modulator in P. aeruginosa, which highlights its potential as a dual-target antimicrobial agent capable of simultaneously restricting bacterial proliferation and disrupting virulence networks.