Journal of Molecular Cell Biology最新文献

Recent advances have revealed that cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS), classically recognized as a cytosolic DNA sensor, plays crucial roles beyond innate immunity. Particularly in the adipose tissue, cGAS functions as a metabolic sentinel, responding to mitochondrial stress and contributing to inflammation, insulin resistance, and energy imbalance. These effects occur through both stimulator of interferon genes (STING)-dependent and STING-independent pathways, involving autophagy, chromatin remodeling, and transcriptional reprogramming. Here, we propose a paradigm shift positioning cGAS at the intersection of immunity and metabolism. We explore its multifaceted roles in adipocytes and other metabolic tissues, highlighting emerging therapeutic opportunities and future research directions.

Enolase 1 (ENO1) is a glycolytic enzyme involved in tumour progression that performs a variety of classical and nonclassical functions. However, the mechanism by which it promotes tumour progression is still not fully understood. Here, we found that ENO1 can bind to β-site amyloid precursor protein cleaving enzyme 2 (BACE2), a codependent gene of ENO1, in liver cancer cells. By suppressing lysosomal-dependent degradation, ENO1 stabilizes BACE2 protein level without affecting its messenger RNA level. Further analysis revealed that ENO1 and BACE2 promote low-density lipoprotein receptor (LDLR) cleavage, leading to decreased absorption of exogenous cholesterol. To maintain intracellular cholesterol levels, ENO1 and BACE2 upregulate the expression of genes involved in de novo cholesterol synthesis through a negative feedback mechanism. Both in vitro and in vivo, BACE2 mediates the tumour-promoting effect of ENO1 in liver cancer. Finally, high expression levels of ENO1 and BACE2 and low expression levels of LDLR were detected in clinical hepatocellular carcinoma samples, and abnormal expression of the ENO1-BACE2-LDLR axis was significantly associated with poor prognosis in patients with liver cancer. These data collectively demonstrated that ENO1 functions in protein cleavage by binding to BACE2 and promotes liver cancer progression by reprogramming cholesterol metabolism.

Ammonia, traditionally recognized as a toxic nitrogen waste product, has recently emerged as a significant player in diverse physiological processes and implicated in cancer biology. This review article provides an overview of the multifaceted impact of ammonia on cellular signaling pathways, energy metabolism, and tumor microenvironment dynamics, in particular its novel roles in neurotransmission, metabolic homeostasis, cancer cell proliferation, and immune modulation. Notably, ammonia accumulates within the tumor microenvironment, promoting nonessential amino acid synthesis, stimulating mTORC1 activation, promoting lipid synthesis, and impairing various immune cell functions, thereby promoting tumor progression. Furthermore, the potential dual role of ammonia as a tumorigenic factor and a cancer therapeutic target is discussed, shedding light on its complex regulatory mechanisms and clinical implications. This timely review aims to deepen our understanding of the emerging physiological and pathological roles of ammonia, offering valuable insights into its significance as a potential target for diagnostic and therapeutic interventions in cancer and beyond.

Upon injury, fibroblasts in the surrounding tissue become activated, migrating into the wound in a controlled manner. Once they arrive, they contract the wound and remodel the stroma. While certain cell surface receptors promote fibroblast migration, others cause repulsion between fibroblasts upon contact, seemingly opposing their clustering within the wound bed. Eph receptor-ephrin interactions on colliding cells trigger this repulsion, but how fibroblasts transition to clustering behaviour during healing remains unclear. Syndecan-4 modulates transmembrane receptors involved in wound healing, including receptors for the extracellular matrix and growth factors. As a result, Sdc4-/- mice experience delayed healing due to impaired fibroblast recruitment. In this study, we report that syndecan-4 also regulates fibroblast repulsion during wound healing. We discover that syndecan-4 inhibits the expression and signalling of EphA2 by activating PKCα. Changes in syndecan-4 expression, such as those observed during wound healing, alter fibroblast behaviour from repulsion to adhesion upon cell collision by modulating EphA2 levels. Moreover, we find that EphA2 expression is suppressed in wound bed fibroblasts in a syndecan-4-dependent manner, explaining how fibroblast clustering is achieved during wound healing.

Septins, components of the fourth cytoskeleton, play an indispensable role in establishing and maintaining epithelial cell polarity. However, the molecular mechanisms underlying the dynamic assembly of higher-order septin structures and the establishment of epithelial cell polarity remain elusive. Here, we show that septins form a previously unrecognized dynamic structure with liquid-like properties in polarized Madin-Darby canine kidney cells. We identified Septin 6 (SEPT6) as the key human septin that undergoes liquid-liquid phase separation (LLPS) both in vitro and in vivo through weak, multivalent interactions mediated by its C-terminal tail. SEPT6 mutants defective in LLPS in vitro also fail to support adherens junction integrity and cell polarity establishment in 2D and 3D cell cultures. Our findings indicate that weak, multivalent interactions are essential for the assembly of higher-order septin structures in cells. We propose that these interactions, in conjunction with conventional interactions between folded domains, generate partially ordered septin assemblies that support the apical-basal axis and lumen formation in metazoans.

The zygotic genome activation (ZGA) is crucial for the development of pre-implantation embryos. Long noncoding RNAs (lncRNAs) play significant roles in many biological processes, but the study on their role in the early embryonic development of pigs is limited. In this study, we identify lncFKBPL as an enhancer-type lncRNA essential for pig embryo development. lncFKBPL is expressed from the 4-cell stage to the morula stage in pig embryos, and interference with lncFKBPL leads to a developmental arrest at the 8-cell stage. Mechanistic investigations uncover that lncFKBPL is able to bind to MED8, thereby mediating enhancer activity and regulating FKBPL expression. Additionally, FKBPL interacts with the molecular chaperone protein HSP90AA1, stabilizing CDK9 and boosting its protein-level expression. Elevated CDK9 levels enhance Pol II phosphorylation, facilitating ZGA. Our findings illuminate the role of lncFKBPL as an enhancer lncRNA in pig ZGA regulation and early embryo development, providing a foundation for further exploration in this area.

Tumor immunotherapy has emerged as a formidable strategy, demonstrating substantial achievements in the field of cancer treatment. Despite its remarkable success, intrinsic limitations such as insufficient targeting capabilities, side effects, and resistance to immunotherapy hinder its efficacy. To address these challenges, the utilization of nanomedicines in tumor immunotherapy has been broadly explored, capitalizing on their advantages of targeting delivery capability, loading capacity, modifiability, and biocompatibility. Through rational design approaches, nanomedicines are engineered to meet diverse delivery requirements and synergize with different regimens to maximize therapeutic efficacy while alleviating side effects. This review initially discusses the challenges associated with tumor immunotherapy and underscores the pivotal role played by nanomedicines in overcoming these obstacles. Subsequently, representative types of nanoparticles are systematically introduced based on their structural properties, advantages, potential limitations, and future research directions. Special emphasis is placed on recent advancements in a range of nanomedicines designed for specific tumor immunotherapy strategies. Finally, the clinical applications as well as prospects of nanomedicines are discussed.

Before committing to an erythroid cell lineage, hematopoietic stem cells differentiate along a myeloid cell pathway to generate megakaryocyte-erythroid biopotential progenitor cells in bone marrow. Recent studies suggest that erythroid progenitors (EryPs) could be generated at the level of common myeloid progenitors (CMPs). However, due to a lack of suitable markers, little is known about the early differentiation of these committed EryP cells during CMP development. Herein, using miR-144/451-eGFP knock-in mice, we found that early differentiation of committed erythroid cells could be defined by miR-144/451 expression within CMPs. Single-cell RNA sequencing showed that miR-144/451+ progenitors show obvious differentiation characteristics of erythroid lineage cells and diverge from megakaryocyte and other myeloid cell lineages. These progenitors exclusively give rise to erythroid cells, both in vitro and in vivo, and the commitment to an erythroid cell lineage is accompanied by loss of CD53 expression. Our findings will facilitate further understanding of the molecular mechanisms governing erythroid development and support the identification of therapeutic targets for diseases related to erythrocyte development.