Advances in biological regulation最新文献

Phosphatidic acid (PA) has emerged as a central regulator of membrane dynamics, vesicle trafficking, exocytosis, and intracellular signaling. Building on recent advances, including subspecies-specific functions of PA in neuroendocrine exocytosis, the primacy of PLD1-derived PA in vivo, and the development of natural-mimetic PA analogues, this review integrates biochemical, biophysical, and systems-level insights across eukaryotes. We contextualize the role of PA in vesicular trafficking, delineate how acyl-chain composition encodes molecular specificity, summarize enzymatic sources and sinks sculpting spatiotemporal control of PA pools within cells, and examine emerging tools used for measuring and disturbing PA in living cells to unravel its function. Given the pleiotropic roles of PA among numerous experimental contexts such as the nervous, endocrine, immune, and metabolic systems, mapping mechanistic connections to disease through mTOR and RAF/MEK/ERK signaling, autophagy, and organelle contact-site biology. Finally, we outline future directions spanning single-cell lipidomics, imaging mass spectrometry, and therapeutic lipid engineering. Together, available evidence positions PA as a conserved, tunable molecular switch that coordinates membrane mechanics with signal transduction to enable realisation of a wide range of function within cells.

The Endosomal Sorting Complex Required for Transport (ESCRT) machinery orchestrates a wide range of membrane remodeling and repair events, spanning multivesicular body biogenesis, viral budding, nuclear envelope surveillance, cytokinesis, lysosomal repair and plasma membrane resealing. These processes depend on the hierarchical assembly of ESCRT complexes to detect and remodel membranes, ultimately driving membrane scission with topological precision. A growing body of evidence indicates that phosphoinositides (PtdIns), a versatile class of phosphorylated lipids, are central determinants of ESCRT function by defining membrane identity, recruiting specific ESCRT modules and integrating lipid signaling into biological processes. This review synthesizes current understanding of how distinct phosphoinositide pools govern ESCRT recruitment and activity, with a focus on the molecular components and their interaction.

Canonically known both for structural contributions to lipid bilayers and roles in cell signaling, the sphingolipids comprise a dynamic, multifaceted class of molecules which are studied to understand cell biology and pathophysiology. All sphingolipids are downstream products of the rate-limiting and initiating enzyme in the de novo sphingolipid synthesis pathway, serine palmitoyltransferase (SPT). SPT activity is strictly regulated. This regulation is accomplished through the ORMDLs, transmembrane polypeptides embedded in the lipid bilayer of the endoplasmic reticulum, which are the regulatory subunits of the SPT complex. Recently the specific mechanism of ORMDL's regulation of SPT was established: ceramide, a downstream product of the de novo biosynthetic pathway, binds directly to a binding site of ORMDL to induce an inhibitory conformational change. Here, we validate a computational docking approach to interrogate the binding efficiency of a range of sphingolipids in the ceramide binding site. We demonstrate that docking poses predicted by this in silico approach reflect experimental data on the efficiency of sphingolipid species to accomplish ORMDL-dependent inhibition of SPT. We propose that this docking analysis will be a valuable complement to experimental tests of compounds that bind to this site to regulate sphingolipid biosynthesis.

DNA double-strand breakage is the most lethal damage to chromosomal DNA. It activates a series of cellular DNA damage response pathways, including DNA damage sensing, control of cell cycle arrest and apoptosis, and DNA repair. DNA damage response pathways are regulated by complex signaling machineries. Of the intracellular signaling cascades, diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Because both DG and PA serve as second messengers, DGK activity induces a shift of signaling pathways from DG-mediated to PA-mediated cascades, thereby implicating DGK in the regulation of widely various functions. Reportedly, one member of the DGK family, DGKζ, is intimately involved in the regulation of stress responses through p53 and NF-κB. Stresses such as ischemia and infarction cause DGKζ downregulation. Experimental DGKζ depletion renders cells and mice vulnerable to various stressors such as chemotherapeutic agents and ionizing irradiation. Nevertheless, how DGKζ is involved in DNA repair, a critical event of DNA damage response for survival remains unknown. For this study, we examined how DGKζ depletion affects DNA repair mechanisms. We demonstrated that DGKζ depletion causes attenuation of Akt activation and DNA-PK protein expression upon DNA damage, which might engender downregulated BRCA1 protein synthesis and stability. Results suggest that DGKζ depletion attenuates BRCA1-mediated DNA repair machinery, thereby conferring vulnerability to DNA damage.

Despite decades of research since phorbol esters first linked protein kinase C (PKC) to tumor promotion, the biological role of this family of kinases in cancer has remained ambiguous because of isozyme-specific functions and tissue-type-dependent effects. Here, we delineate critical roles for PKC in lung cancer. We previously showed that sustained activation of PKCβ_II activates mTOR, an effect evident in lung cancer cell lines with high expression of classical PKCs (cPKCs). These findings prompted us to examine lung cancers driven by mutant EGFR (mEGFR), in which PKCα is highly expressed. We find that mEGFR-dependent activation of PKCα drives serum-deprived proliferation, anchorage-independent growth (AIG), and anchorage-independent survival (AIS). Subsequent studies revealed that the mutant receptor is impaired in ligand-independent activation and, due to altered autophosphorylation, exhibits biased activation of the PLC arm, preferentially propagating signals through a PLC-PKCα-AKT-mTORC1 axis required for AIG and AIS. In parallel, we investigated the basis of PKCα upregulation and found that elevated PKCα levels are independent of mEGFR. Bioinformatic analysis of mEGFR lung cancers highlighted basal cells, a subtype of lung cell which intrinsically express high PRKCA, as the likely cell-of-origin, suggesting that cell lineage sets a high ceiling for PKCα abundance, while mEGFR licenses the activation of the kinase. Collectively, these data define a pathway-specific role for cPKCs, particularly PKCα, as upstream effectors of mTORC1 in mEGFR systems, establishing a neomorphic dependency on the PKCα-AKT-mTORC1 signaling arm that sustains tumorigenesis via biased signaling by the mutant receptor.

The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as an essential post-translational modification in mammals. More than 5000 human proteins are subject to O-GlcNAcylation, influencing key cellular processes such as signal transduction, epigenetic regulation, transcription, translation, and bioenergetics. Dysregulation of this modification has been implicated in a wide range of diseases, including metabolic disorders, cancer, neurodegeneration, ischemic injury, and heart failure. O-GlcNAc-cycling is orchestrated by two enzymes: the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and removal of O-GlcNAc, respectively. A central challenge in the field is understanding how this minimal enzymatic machinery achieves such broad substrate specificity. It is hypothesized that OGT's functional versatility is mediated through interactions with a diverse network of protein partners that act as adaptors, scaffolds, or substrates, thereby directing its localization, modulating its activity, and shaping its substrate selectivity. In this review, we discuss key interactors and their functional impact on OGT. We also explore how post-translational modifications and substrate availability contribute to OGT regulation and specificity.

The pancreatic islet, historically described as a binary system of insulin-secreting beta cells and glucagon-secreting alpha cells, is increasingly recognized as a complex paracrine network contributing to glucose homeostasis. Alpha-to-beta cell communication is not merely modulatory but a decisive mechanism sustaining islet function under metabolic stress. Alpha cell distribution, structural specializations at the alpha-beta interface, and adaptations in signaling pathways collectively shape glycemic set points and beta cell resilience. Recent studies highlight the context-dependent nature of this intra-islet crosstalk. Visa et al. demonstrated that prediabetic stress in Western diet-fed mice remodels islet cytoarchitecture in a sex-dependent manner, enhancing alpha-to-beta signaling and Ca²⁺ dynamics, and thereby preserving insulin secretion more effectively in females than in males. Experiments using a glucagon receptor antagonist in human islets confirmed that glucagon paracrine signaling is essential for this adaptive enhancement, particularly the increased Ca²⁺ dynamics in female islets under high metabolic demand. Mechanistic studies further revealed that the GLP-1 receptor forms specialized nanodomains at the alpha-beta junction that undergo pre-internalization, priming beta cells for rapid Ca²⁺ influx and heightened metabolic responsiveness. Collectively, these findings highlight intra-islet communication as a critical determinant of adaptation or failure in diabetes progression. However, conflicting evidence from beta cell-only islets, which display enhanced glucose-stimulated insulin secretion, together with reports that long-term exposure to the GLP-1 analog liraglutide can compromise beta cell function, presents a paradox that challenges current models of intra-islet regulation. Understanding these nuances is crucial for translating intra-islet signaling into targeted therapeutic strategies and regenerative tissue engineering.

CD19 is a central regulator of B-cell biology, acting both as a lineage marker and a critical modulator of signaling thresholds that govern development, activation, and tolerance. Structurally, CD19 is a heavily glycosylated transmembrane protein whose cytoplasmic domain harbors multiple tyrosine motifs serving as docking sites for key signaling molecules, including PI3K. Its expression is tightly regulated by transcriptional, post-transcriptional, and post-translational mechanisms, as well as by interactions with CD21 and CD81 in surface complexes. Genetic studies in mice and humans demonstrate that CD19 acts as a molecular rheostat, with both deficiency and overexpression leading to profound immunological dysfunctions ranging from hypogammaglobulinemia to autoimmunity. Importantly, recent work has revealed an additional level of CD19 signaling regulation mediated by conformational control of the CD19 cytoplasmic domain. A basic CD19 cytoplasmic juxtamembrane region engages in ionic interactions with PtdIns(4,5)P2, thereby influencing CD19 activation state. Loss of the 5-phosphatase INPP5K increases PtdIns(4,5)P2 levels, leading to constitutive CD19 signaling, impaired B-cell development and hypogammaglobulinemia. This discovery underscores the role of lipid-protein interactions in restraining inappropriate CD19 activation. Clinically, CD19 has emerged as a validated therapeutic target, with CAR T cells, bispecific antibodies, and monoclonal antibodies achieving remarkable efficacy in B-cell malignancies and autoimmune disorders. Understanding the fine regulation of CD19 expression, structure, and signaling remains essential to optimize therapeutic strategies.

The myelodysplastic syndromes (MDS) are common myeloid malignancies that develop from the successive acquisition of driver mutations in hematopoietic stem cells residing in the bone marrow. Around a third of MDS patients will develop secondary acute myeloid leukemia (sAML) and patients with high-risk MDS or sAML have a dismal prognosis. The study of disease progression in myeloid malignancy has been enhanced in recent years by the use of induced pluripotent stem cells (iPSCs) technology. iPSCs offer the advantage of indefinite expansion and the potential for genetic modification, with reprogramming enabling the capture of the full complement of genetic lesions found in primary patient bone marrow samples. The power of iPSC and CRISPR-Cas9 gene editing technologies have been harnessed to generate a range of iPSC-based cellular models of MDS, reflecting the genetic and biologic heterogeneity of the disease. Stage-specific patient iPSC lines have been produced and sequential gene editing in normal human iPSCs has been performed to map the evolution of MDS to AML. These studies have increased our understanding of the impact of driver mutations, and co-mutations, on disease phenotype and revealed mechanisms underlying disease stage transitions in myeloid malignancy. iPSC-based models of MDS have also proven important tools in high throughput drug screening and have empowered drug testing and drug discovery, offering a new platform to develop personalized therapy.

Genetic alterations in genes encoding components of the PI3K/AKT/mTOR signaling pathway are frequently observed in head and neck squamous cell carcinoma (HNSCC), breast cancer, and a variety of other human malignancies. In particular, PIK3CA, encoding the p110α catalytic subunit of PI3K enzyme, is altered in approximately 30 % of HNSCC tumors and 37 % of breast cancer tumors. In addition, loss of PTEN protein, a negative regulator of PI3K signaling, occurs in roughly one-third of HNSCC. Here, we review the impact of these alterations on the growth and metabolism of cancer cells and summarize progress that has been made in the development and clinical evaluation of inhibitors that directly target p110α and related proteins. We also describe emerging approaches that are identifying unique vulnerabilities and targeting opportunities in tumors characterized by PIK3CA or PTEN alterations.