Cell reports最新文献

Transport through the nuclear pore complex (NPC) relies on intrinsically disordered FG-nucleoporins (FG-Nups) forming a selective barrier. Away from the NPC, FG-Nups readily form condensates and aggregates, and we address how this behavior is surveilled in cells. FG-Nups, including Nsp1, together with the nuclear transport receptor Kap95, form a native daughter cell-specific cytosolic condensate in yeast. In aged cells, this condensate disappears as cytosolic Nsp1 levels decline. Biochemical assays and modeling show that Nsp1 is a modulator of FG-Nup condensates, promoting a liquid-like state. Nsp1's presence in the cytosol and condensates is critical, as a reduction of cytosolic levels in young cells induces NPC defects and a general decline in protein quality control that quantitatively mimics aging phenotypes. These phenotypes can be rescued by a cytosolic form of Nsp1. We conclude that Nsp1 is a phase state regulator that surveils FG-Nups and impacts general protein homeostasis.

Although adenosine deaminase 2 (ADA2) is considered an extracellular ADA, evidence questions the physiological relevance of this activity. Our study reveals that ADA2 localizes within the lysosomes, where it is targeted through modifications of its glycan structures. We show that ADA2 interacts with DNA molecules, altering their sequences by converting deoxyadenosine (dA) to deoxyinosine (dI). We characterize its DNA substrate preferences and provide data suggesting that DNA, rather than free adenosine, is its natural substrate. Finally, we demonstrate that dA-to-dI editing of DNA molecules and ADA2 regulate lysosomal immune sensing of nucleic acids (NAs) by modulating Toll-like receptor 9 (TLR9) activation. Our results describe a mechanism involved in the complex interplay between NA metabolism and immune response, possibly impacting ADA2 deficiency (DADA2) and other diseases involving this pathway, including autoimmune diseases, cancer, or infectious diseases.

Upon infection with herpes simplex virus 1 (HSV-1), the virus deploys multiple strategies to evade the host's innate immune response. However, the mechanisms governing this phenomenon remain elusive. Here, we find that HSV-1 leads to a decrease in overall m6A levels by selectively reducing METTL14 protein during early infection in glioma cells. Specifically, the HSV-1-encoded immediate-early protein ICP0 interacts with METTL14 within ND10 bodies and serves as an E3 ubiquitin protein ligase, targeting and ubiquitinating METTL14 at the lysine 156 and 162 sites. Subsequently, METTL14 undergoes proteasomal degradation. Furthermore, METTL14 stabilizes ISG15 mRNA mediated by IGF2BP3 to promote antiviral effects. Notably, METTL14 suppression significantly enhances the anti-tumor effect of oncolytic HSV-1 (oHSV-1) in mice bearing glioma xenografts. Collectively, these findings establish that ICP0-guided m6A modification controls the antiviral immune response and suggest that targeting METTL14/ISG15 represents a potential strategy to enhance the oncolytic activity of oHSV-1 in glioma treatment.

During periods of nutrient scarcity, many animals undergo germline quiescence to preserve reproductive capacity, and neurons are often necessary for this adaptation. We show here that starvation causes the release of neuronal microRNA (miRNA)/Argonaute-loaded exosomes following AMP kinase-regulated trafficking changes within serotonergic neurons. This neuron-to-germline communication is independent of classical neurotransmission but instead relies on endosome-derived vesicles that carry a pro-quiescent small RNA cargo to modify germline gene expression. Using an miRNA activity sensor, we show that neuronally expressed miRNAs can extinguish the expression of germline mRNA targets in an exosome-dependent manner. Our findings demonstrate how an adaptive neuronal response can change gene expression at a distance by redirecting intracellular trafficking to release neuronal exosomes with specific miRNA cargoes capable of tracking to their appropriate destinations.

Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication, leading to transcription-replication conflicts (TRCs). Here, we demonstrate that TRCs are enriched in human pancreatic ductal adenocarcinoma (PDAC) compared to other common solid tumors or normal cells. Several orthogonal approaches demonstrated that TRCs are oncogene dependent. A small interfering RNA (siRNA) screen identified several factors in the base-excision repair (BER) pathway as main regulators of TRCs in PDAC cells. Inhibitors of BER pathway (methoxyamine and CRT) enhanced TRCs. Mechanistically, BER pathway inhibition severely altered RNA polymerase II (RNAPII) and R-loop dynamics at nascent DNA, causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated the ATR-Chk1 pathway. Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study provides mechanistic insights into the regulation of TRCs in PDAC by the BER pathway, which has biologic and therapeutic implications.

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 C. elegans recombinant inbred advanced intercross lines (RIAILs). We assessed molecular profiles-transcriptome, proteome, and lipidome-and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which correlated positively with developmental time. We validated three longevity modulators, including rict-1, gfm-1, and mltn-1, among the top candidates obtained from multiomics data integration and quantitative trait locus (QTL) mapping. We translated their relevance to humans using UK Biobank data and showed that variants in GFM1 are associated with an elevated risk of age-related heart failure. We organized our dataset as a resource that allows interactive explorations for new longevity targets.

Phytohormone abscisic acid (ABA) regulates key plant development and environmental stress responses. The ubiquitin-proteasome system tightly controls ABA signaling. CULLIN4-RING (CRL4) E3 ubiquitin ligases use the substrate receptor module CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP10)-DDB1-DET1-DDA1 (CDDD) to target Arabidopsis ABA receptor PYL8, acting as negative regulators of ABA responses. Conversely, ABA treatment attenuates PYL8 receptor degradation, although the molecular mechanism remained elusive. Here, we show that ABA promotes the disruption of CRL4-CDDD complexes, leading to PYL8 stabilization. ABA-mediated CRL4-CDDD dissociation likely involves an altered association between DDA1-containing complexes and the COP9 signalosome (CSN), a master regulator of the assembly of cullin-based E3 ligases, including CRL4-CDDD. Indeed, treatment with CSN inhibitor CSN5i-3 suppresses the ABA effect on CRL4-CDDD assembly. Our findings indicate that ABA stabilizes PYL8 by altering the dynamics of the CRL4-CDDD-CSN complex association, showing a regulatory mechanism by which a plant hormone inhibits an E3 ubiquitin ligase to protect its own receptors from degradation.

Despite increasing reports of convergent adaptation, evidence for genomic convergence across diverse species worldwide is lacking. Here, our study of 205 Archaeplastida genomes reveals evidence of genomic convergence through tandem duplication (TD) across different lineages of root plants despite their genomic diversity. TD-derived genes, notably prevalent in trees with developed root systems embedded in soil, are enriched in enzymatic catalysis and biotic stress responses, suggesting adaptations to environmental pressures. Correlation analyses suggest that many factors, particularly those related to soil microbial pressures, are significantly associated with TD dynamics. Conversely, flora transitioned to aquatic, parasitic, halophytic, or carnivorous lifestyles-reducing their interaction with soil microbes-exhibit a consistent decline in TD frequency. This trend is further corroborated in mangroves that independently adapted to hypersaline intertidal soils, characterized by diminished microbial activity. Our findings propose TD-driven genomic convergence as a widespread adaptation to soil microbial pressures among terrestrial root plants.

Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.

There are only a few effective molecular targeted agents for advanced unresectable or recurrent advanced gastric cancer (AGC), which has a poor prognosis with a median survival time of less than 14 months. Focusing on phosphorylation signaling in cancer cells, we have been developing deep phosphoproteome analysis from minute endoscopic biopsy specimens frozen within 20 s of collection. Phosphoproteomic analysis of 127 fresh-frozen endoscopic biopsy samples from untreated patients with AGC revealed three subtypes reflecting different cellular signaling statuses. Subsequent serial biopsy analysis has revealed the dynamic mesenchymal transitions within cancer cells, along with the concomitant rewiring of the kinome network, ultimately resulting in the conversion to the epithelial-mesenchymal transition (EMT) subtype throughout treatment. We present our investigation of intracellular signaling related to the EMT in gastric cancer and propose therapeutic approaches targeting AXL. This study also provides a wealth of resources for the future development of treatments and biomarkers for AGC.