Cell reports最新文献

Hepatitis B infection can lead to liver fibrosis and hepatocellular carcinoma (HCC). Despite antiviral therapies, some patients still develop HCC. This study investigates hepatitis B virus (HBV)-induced hepatocyte-hepatic stellate cell (HSC) crosstalk and its role in liver fibrosis and HCC. Using MYC-driven liver cancer stem cell organoids, HCC-patient-derived xenograft (PDX) models, and HBV replication models, this study reveals that HBV transcription affected hepatocyte development, activated the DNA repair pathway, and promoted glycolysis. HBV activated nicotinamide phosphoribosyltransferase (NAMPT) through DNA damage receptor ATR. NAMPT-insulin receptor (INSR)-mediated hepatocyte-HSC crosstalk caused HSCs to develop a myofibroblast phenotype and activated telomere maintenance mechanisms via PARP1 multisite lactylation. Inhibition of the ATR-NAMPT-INSR-PARP1 pathway effectively blocks HBV-induced liver fibrosis and HCC progression. Targeting this pathway could be a promising strategy for chronic HBV infection management.

Plant lipids are an essential energy source for diets and are a sustainable alternative to petroleum-based fuels and feedstocks. Fatty acid breakdown during seed germination is crucial for seedling establishment but unexpected during seed filling. Here, we demonstrate that the simultaneous biosynthesis and degradation of fatty acids begins early and continues across all phases of oil filling and throughout the photoperiod. Tests in camelina, rapeseed, and an engineered high-oil tobacco line confirmed that concomitant synthesis and breakdown in oil-producing tissues over development is the rule rather than the exception. Furthermore, we show that transgenics, designed to elevate fatty acid biosynthesis, failed to achieve anticipated increases in storage lipid levels due to increased degradation, potentially explaining the underperformance of engineered lines compared to expectations more generally.

The NAIP/NLRC4 inflammasome plays a pivotal role in the defense against bacterial infections, with its in vivo physiological function primarily recognized as driving inflammation in immune cells. Acute lung injury (ALI) is a leading cause of mortality in sepsis. In this study, we identify that the NAIP/NLRC4 inflammasome is highly expressed in both macrophages and pulmonary fibroblasts and that pyroptosis of these cells plays a critical role in lung injury. Mice challenged with gram-negative bacteria or flagellin developed lethal lung injury, characterized by reduced blood oxygen saturation, disrupted lung barrier function, and escalated inflammation. Flagellin-induced lung injury was protected in caspase-1 or GSDMD-deficient mice. These findings enhance our understanding of the NAIP/NLRC4 inflammasome's (patho)physiological function and highlight the significant role of inflammasome activation and pyroptosis in ALI during sepsis.

Cisplatin (CDDP) is a widely used chemotherapy drug for treating various solid tumors. However, resistance to CDDP significantly hampers patient outcomes. This study reveals that protein arginine methyltransferase (PRMT)5 methylates METTL3 at the R36 residue (METTL3-R36me2), which is crucial for CDDP resistance in ovarian cancer (OC) cells. Following CDDP exposure, MST4 is transactivated by nuclear factor-erythroid 2-related factor 2 (NRF2), a key regulator of antioxidant responses. MST4 stimulates PRMT5's methyltransferase activity and promotes its interaction with METTL3 via phosphorylation at Ser439 and Ser463, resulting in increased levels of METTL3-R36me2 and mRNA methylation at the N6 position of adenosine (m⁶A). The METTL3-R36me2 is recruited to DNA damage sites to promote RAD51 recruitment for homologous recombination (HR)-mediated double-strand break repair (DSBR) and enhance CDDP resistance. Importantly, targeting METTL3-R36me2 through inhibition of PRMT5 or METTL3 disrupts HR-DSBR and augments the cytotoxic effects of CDDP in ovarian tumor xenografts. Therefore, we conclude that METTL3-R36me2 represents a viable therapeutic target for overcoming CDDP resistance in OC.

G protein-coupled receptor 3 (GPR3) is a class A orphan receptor characterized by high constitutive activity in the G_s signaling pathway. GPR3 has been implicated in Alzheimer's disease and the regulation of thermogenesis in human adipocytes, yet the molecular mechanisms underlying its self-activation and potential endogenous modulators remain unclear. In this study, we present cryo-electron microscopy (cryo-EM) structures of GPR3 in different oligomerization states, both in the absence and presence of G protein. Notably, in addition to the monomeric form of GPR3, our findings reveal a functional GPR3 dimer with an extensive dimer interface-a feature rarely observed in class A GPCRs. Moreover, oligomerization appears to be linked to a unique autoinhibition mechanism involving intracellular loops, which may regulate GPR3 signaling. Collectively, these results provide new insights into the oligomerization-modulated activation of orphan GPCRs, advancing our understanding of their signaling properties.

Building synaptic connections requires coordinating a host of cellular activities from cell signaling to protein turnover, placing a high demand on intracellular communication. Membrane contact sites (MCSs) formed between organelles have emerged as key signaling hubs for coordinating diverse cellular activities, yet their roles in the developing nervous system remain obscure. We investigate the in vivo function of the endoplasmic reticulum (ER) MCS tethering and lipid-transfer protein PDZD8, which was recently linked to intellectual disability, in the nervous system. We find that PDZD8 is required for activity-dependent synaptic bouton formation in multiple paradigms. PDZD8 is sufficient to drive excess synaptic bouton formation through an autophagy-dependent mechanism and required for synapse development when autophagy is limited. PDZD8 accelerates autophagic flux by promoting lysosome maturation at ER-late endosome/lysosome MCSs. We propose that PDZD8 functions in the nervous system to increase autophagy during periods of high demand, including activity-dependent synaptic growth.

The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. In particular, three ZNF410 motifs (sub-HCTs) located at 3' end of the distal enhancer act as "switch motifs" to control chromatin accessibility and enhancer activity. Mechanistically, the SWI/SNF complex is selectively required to mediate cooperative ZNF410 binding for CHD4 expression. Together, our findings expose a complex functional hierarchy of homotypic clustered motifs, which cooperate to fine-tune target gene expression.

Zika virus (ZIKV) vertical transmission results in devastating congenital malformations and pregnancy complications; however, the specific receptor and host factors facilitating ZIKV maternal-fetal transmission remain elusive. Here, we employ a genome-wide CRISPR screening and identify multiple placenta-intrinsic factors modulating ZIKV infection. Our study unveils that hepatitis A virus cellular receptor 1 (HAVCR1) serves as a primary receptor governing ZIKV entry in placental trophoblasts. The GATA3-HAVCR1 axis regulates heterogeneous cell tropism in the placenta. Notably, placenta-specific Havcr1 deletion in mice significantly impairs ZIKV transplacental transmission and associated adverse pregnancy outcomes. Mechanistically, the immunoglobulin variable-like domain of HAVCR1 binds to ZIKV via domain III of envelope protein and virion-associated phosphatidylserine. Proteomic profiling and function analyses reveal that AP2S1 cooperates with HAVCR1 for ZIKV internalization through clathrin-mediated endocytosis. Overall, our work underscores the pivotal role of HAVCR1 in mediating ZIKV vertical transmission and highlights a therapeutic target for alleviating congenital Zika syndrome.

Antibody effector functions contribute to the immune response to pathogens and can influence the efficacy of antibodies as therapeutics. To date, however, there is limited information on the molecular parameters that govern fragment crystallizable (Fc) effector functions. In this study, using AI-assisted protein design, the influences of binding kinetics, epitope location, and stoichiometry of binding on cellular Fc effector functions were investigated using engineered HIV-1 envelope as a model antigen. For this antigen, stoichiometry of binding was found to be the primary molecular determinant of FcγRIIIa signaling, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis, while epitope location and antibodybinding kinetics, at least in the ranges investigated, were of no substantial impact. These findings are of importance for informing the development of vaccination strategies against HIV-1 and, possibly, other viral pathogens.

High-intensity alcohol drinking during binge episodes contributes to the socioeconomic burden created by alcohol use disorders (AUDs), and nociceptin receptor (NOP) antagonists have emerged as a promising intervention. To better understand the contribution of the NOP system to binge drinking, we found that nociceptin-containing neurons of the lateral septum (LS^Pnoc) displayed increased excitability during withdrawal from binge-like alcohol drinking. LS^Pnoc activation promoted active avoidance and potentiated binge-like drinking behavior, whereas silencing of this population reduced alcohol drinking. LS^Pnoc form robust monosynaptic inputs locally within the LS and genetic deletion of NOP or microinjection of a NOP antagonist into the LS decreased alcohol intake. LS^Pnoc also project to the lateral hypothalamus and supramammillary nucleus of the hypothalamus, and genetic deletion of NOP from each site reduced alcohol drinking. Together, these findings implicate the septo-hypothalamic nociceptin system in excessive alcohol consumption and support NOP antagonist development for the treatment of AUD.