Communications Biology最新文献

The NF-κB pathway plays a critical role in mediating the innate immune response downstream of activated immune receptors such as the TNFαR. Activation of this pathway is induced by several ubiquitin ligases (e.g., cIAP, TRAFs, NEMO, β-TrCP, KPC1), including Nedd4-1. Nedd4-1 comprises a C2-WW(4)-HECT domain architecture. We recently characterized a primate-specific splice isoform of Nedd4-1, Nedd4-1(NE), in which the C2 domain is replaced by a large N-terminally Extended (NE) region. Using miniTurbo BioID, we identified here several components of the NF-κB pathway in complex with Nedd4-1(NE) (but not with the canonical Nedd4-1), including IKKα/β and p105-NF-κB1. We further show that (i) Nedd4-1(NE) ubiquitinates and promotes degradation of IKKβ, therefore inhibiting phosphorylation and promoting stability of its substrate, the inhibitory IκBα; (ii) active Nedd4-1(NE) binds and destabilizes NF-κB1, an interaction that is dependent upon Nedd4-1(NE)-mediated KPC1 ubiquitination. Furthermore, KPC1 promotes translocation of NF-κB1 to late endosomal membranes, where Nedd4-1(NE) resides, to facilitate the Nedd4-1(NE): NF-κB1 interaction. Consequently, Nedd4-1(NE)-mediated regulation of both IKKβ and NF-κB1 suppresses NF-κB1 nuclear translocation and activation of its target genes; and (iii) Nedd4-1(NE) (but not canonical Nedd4-1) mRNA expression is increased upon prolonged TNFα treatment of cells. This work uncovered an E3 ubiquitin ligase that suppresses the NF-κB1 pathway to ensure termination of this pro-inflammatory signaling pathway in primates via a negative feedback mechanism; Such an additional layer of immune regulation has important implications for understanding inflammatory homeostasis and its dysregulation in human disease.

The enzymes acetyl-CoA acetyltransferase (ACATs) are membrane-bound enzymes that play critical roles in the regulation of cellular cholesterol homeostasis in various tissues. Here, we aim to assess the effect of ACAT2 on lipid accumulation in cervical cancer (CC). ACAT2 expression is enhanced in CC and is closely associated with the immune evasion and clinical progression of CC. Knockdown of ACAT2 expression in CC cells inhibits CC growth, improves survival in tumor-bearing C57BL/6 mice, and enhances anti-tumor immune responses by natural killer and CD8⁺ T cells. Protein expression of sterol regulatory element-binding transcription factor 2 (SREBF2) is elevated in CC and mediates the transcriptional activation of ACAT2. E3 ubiquitin-protein ligase parkin (PRKN) expression is attenuated in CC, which results in a diminished level of ubiquitination of SREBF2 and enhanced stability of SREBF2. PRKN inhibits cholesterol accumulation in CC, activates mitophagy, and ameliorates immune evasion through inhibition of SREBF2/ACAT2. Overexpression of SREBF2 blocks the anti-tumor effects of PRKN in an ACAT2-dependent manner. The present study underscores the pivotal function of ACAT2 in CC progression and delineates its potential as a therapeutic latent strategy. This approach involves the strategic obstruction of the metabolic pathway associated with ACAT2.

Exceptionally preserved 135-million-year-old ammonoids from the Neuquén Basin at the Andean foothills revealed a fossilised structure never recorded before. Ammonoids are cephalopods that inhabited the oceans for about 400 million years until they became extinct 66 million years ago. Their shells are composed of aragonitic layers bounded externally by an organic periostracum. The latter plays an essential role in initiating shell biomineralisation and protecting minerals from dissolution and abrasion. Here we describe a preserved periostracum in Cretaceous ammonoids, an extremely fragile yet flexible layer, with an approximate thickness of 2 µm and an internal horizontal lamination. The external surface appears mostly smooth, while the internal surface displays a reticulated appearance, interpreted as the casts of aragonite prisms of the calcareous shell. Our results reveal that the ammonoid periostracum contains proteins, polysaccharides, and lipids, consistent with the composition of the periostracum in modern-day molluscs. This study sheds light on a previously little-known organic structure in ammonoids. Its morphological and chemical characteristics allow us to establish that it is a highly conservative structure among molluscs. Furthermore, we show that such a delicate organic structure can be preserved for 135 million years in favourable environmental conditions, opening up the possibility of future discoveries.

The Sec pathway is an essential protein secretion route for all organisms. In bacteria, the SecA ATPase peripherally associates with the SecYEG channel to form the translocase that mediates preprotein export. Activation of the translocase depends strictly on the synergy of signal peptide and mature domain binding. Thus, client selectivity, translocase activation and protein secretion are coupled by one mechanism. We show here that a previously identified small molecule (HSI#6) binds SecA, modulates its intrinsic dynamics and allosterically activates the translocase in the absence of clients. By uncoupling translocase activation from preprotein binding, HSI#6 transformed the translocase into a promiscuous nanomachine that lost client selectivity and secreted unfolded pre- mature- and cytoplasmic- proteins with high efficiency in vivo or in vitro. To our knowledge, HSI#6 is the first activator of the Sec pathway and might offer unique opportunities for the discovery of new antibacterials.

Sleep deprivation (SD) disrupts systemic homeostasis, but how it drives ocular surface disease remains unclear. Using a male mouse SD model, we show that chronic SD activates the hypothalamic-pituitary-adrenal (HPA) axis, elevates corticosterone, alters gut microbiota, and depletes short-chain fatty acids (SCFAs). These alterations coincide with lacrimal gland atrophy, reduced tear secretion, and increased CD4⁺/CD8⁺ T cell infiltration, accompanied by activation of IL-17-associated inflammatory pathways. Pharmacological inhibition of glucocorticoid synthesis with metyrapone preserves lacrimal gland structure and function while attenuating immune activation. Microbiome-directed interventions, including SCFA supplementation and fecal microbiota transplantation, rebalance gut communities, suppress pro-inflammatory T cell responses, and maintain lacrimal gland homeostasis. Transcriptomic and immunohistochemical analyses further reveal that all three interventions converge on the downregulation of IL-17 signaling. Collectively, these findings establish an HPA-gut microbiome-lacrimal gland axis that links neuroendocrine stress to microbial dysbiosis and ocular inflammation, and they suggest therapeutic strategies for SD-associated lacrimal gland dysfunction.

Cells throughout physiological and pathological contexts are exposed to a broad spectrum of mechanical stimuli, triggering extensive nuclear deformation and chromatin remodeling. These mechanical cues drive the cell to dynamically adapt through coordinated structural, epigenetic, and biochemical mechanisms to withstand mechanical stress while protecting genomic integrity. However, whether such cellular adaptations are reversible or result in persistent alterations remains unresolved. In cancer metastasis, addressing this issue is critical: confined migration through narrow pores prompts chromatin condensation with heterochromatin enrichment, yet cancer cells must preserve their oncogenic potential while preparing for future deformations. Therefore, the ability of these cells to reconcile reversible chromatin remodeling and mechanical memory could be key to metastatic resilience. Here, using a custom-designed microfluidic device to monitor single-cell chromatin reorganization, we show confined migration induces partially-reversible chromatin condensation: total highly-condensed chromatin content is recovered after deformation, but the distribution of condensed chromatin clusters remains altered. Our findings highlight this duality of chromatin condensation as both a short-term adaptive response and a mechanical memory strategy, which could potentially contribute to address cancer invasiveness.

CRISPR/Cas9-mediated genome editing has expanded the possibilities for precise gene modifications; however, the efficiency of targeted insertion remains suboptimal. In this study, we describe a triple-reporter system in mouse embryonic stem cells that simultaneously tracks double-strand break (DSB) induction, homology-directed repair (knock-in), and end-joining-mediated targeted insertion (EJ-TI). Using both plasmid and adeno-associated virus (AAV) donor vectors, our results demonstrate that ataxia telangiectasia and Rad3-related kinase (ATR) activity is essential for knock-in regardless of the donor type, whereas ataxia telangiectasia mutated (ATM) inhibition exhibits a donor-dependent role. In cells receiving circular plasmid donors, ATM inhibition with AZD1390 markedly reduced the knock-in and EJ-TI efficiencies, consistent with its canonical role in DSB repair. In contrast, with linear AAV donors, ATM inhibition enhanced the knock-in efficiency by suppressing the overactivation of the ATM-p53-caspase 3 apoptotic pathway and partially suppressing classical non-homologous end-joining. These findings highlight the critical influence of donor DNA configuration on DNA damage response signaling and provide a strategy for optimizing genome editing efficiency by selectively modulating the ATM pathways, an approach that may have significant implications for gene therapy, cell engineering, and other applications.

Insect pest population control via sterile insect technique markedly benefits from separation by sex prior to release. To simplify this process, traditional genetics has been deployed to develop genetic sexing strains (GSSs) for several disease vectors and agricultural pests of vast economic significance, although very few are applied in the field due to associated fitness costs and instability. In this study, we generated a method to engineer cisgenic GSS (CGSS) in insects. We use CRISPR/Cas9-mediated homology-directed repair to seamlessly translocate a sex-specific alternatively spliced intron into a dominant phenotypic gene generating a genetically stable strain that enables sex-sorting by eye. To achieve this feat, we use Ceratitis capitata as our model and relied on the sex-specifically spliced intron of its endogenous transformer gene, which we seamlessly inserted a copy into the pupal colouration white pupae gene. This minimal modification resulted in the generation of a homozygous strain we term IMPERIAL that was genetically and phenotypically stable where all female pupae are brown while male pupae are white with overall good fitness. By minimally editing the genome, our novel CGSS approach can be applied to other pests that may aid more efficient and economically suitable pest control.

Divalent cations such as Mg²⁺ and Ca²⁺ are key modulators of chromatin architecture, yet their atomistic influence on nucleosome structure and histone tail dynamics remains elusive. Here, we present 81 microseconds of all-atom molecular dynamics (MD) simulations to dissect how these ions shape nucleosome dynamics and plasticity. We quantitively mapped the selective binding patterns of Mg²⁺ and Ca²⁺ in nucleosomes with and without histone tails, revealing distinct ion-nucleosome interactions. Notably, divalent ion binding reduces inter-gyre electrostatic repulsion, facilitates DNA gyre compaction, and increases nucleosome stiffness, as quantified by estimates of the Young's modulus and correlated motions within specific DNA regions. Importantly, ion binding weakens histone tail-DNA interactions and enhances tail mobility-particularly that of H3-potentially facilitating access by chromatin regulators and tail-mediated chromatin compaction. These findings reveal a dual role of divalent ions in modulating nucleosome plasticity while reinforcing histone tail dynamics, providing a mechanistic framework for understanding how ionic fluctuations influence gene accessibility and chromatin state.

Photosystem I (PSI) is one of the two photosystems conserved from cyanobacteria to vascular plants, and associates with multiple light-harvesting complexes (LHCs) that capture and transfer solar energy. Liverworts such as Marchantia polymorpha occupy an early evolutionary position among land plants and faced major challenges during terrestrial adaptation, including desiccation, strong light, and UV radiation. We reveal the cryo-electron microscopic structures of PSI-LHCI monomer and homodimer from the liverwort M. polymorpha at resolutions of 1.94 and 2.52 Å, respectively. The high-resolution map allows identification of the cofactors of the monomer and reveal differences between the liverwort and moss, another clade of bryophytes. The PSI-LHCI monomer-monomer is stabilized by PsaG and PsaH interactions on the stromal side, which causes the bending and twisting of the homodimer. PsaM interacts with PsaB tightly, indicating a key role of PsaM in mediating the dimerization.