Trends in Cell Biology最新文献

CD4 T cells orchestrate immune responses through differentiation into specialized helper subsets. Traditionally, CD4 T cell differentiation is described as a linear process in which naïve CD4 T cells commit to distinct effector lineages upon activation. However, growing evidence challenging this paradigm has provoked considerable debate about CD4 T cell plasticity. This review describes the emerging concept of stem-like CD4 T cells and how they update our understanding of the fundamental mechanisms that regulate CD4 T cell differentiation. We discuss how stem-like CD4 T cells play a crucial role as precursor cells to distinct effector subsets and explore their implications in cancer, infections, and autoimmunity. Finally, we address how stem-like CD4 T cells might resolve long-standing questions about CD4 T cell plasticity, and propose alternative differentiation models that incorporate this population in chronic diseases.

Proteoglycans (PGs) are specialized cell-surface and secreted proteins teeming with bioactivity. They have been the subject of fascinating research on autophagy, lymphangiogenesis, and neurodegenerative diseases. PG influence on autophagy extends to several disease domains, and their ability to alter autophagic processes has highlighted their suitability as therapeutic targets. PGs also display new functions by evoking protracted autophagy in lymphatic endothelial cells and inhibiting tumor and physiological lymphangiogenesis. The variable degree of PG sulfation and their ability to regulate growth-factor activities in the central nervous system has opened doors into novel therapeutic avenues including Alzheimer's and Parkinson's diseases. This review systematically integrates these diverse qualities of PGs while highlighting future directions towards clinical application.

Cell cycle checkpoints preventing the replication and inheritance of damaged DNA are crucial for maintaining genome stability and stopping the growth of damaged cells. Canonical checkpoints do this by preventing passage between cell cycle phases until damage has been repaired, or by promoting cell cycle exit. Herein we review checkpoint integration between cell cycle phases, specifically findings showing that extended spindle assembly checkpoint surveillance in mitosis is a danger signal triggering G1 cell cycle arrest. Evidence linking mitotic delays induced by activation of the spindle assembly checkpoint with positive and negative regulators of the G1 DNA damage checkpoint target p53 is discussed, with a focus on time-dependent changes to a p53-binding deubiquitinating complex USP28-53BP1 and the p53 ubiquitin-ligase mouse double minute homologue 2 (MDM2), respectively.

The intricate interplay between Wnt signaling and nicotinamide adenine dinucleotide (NAD⁺⁾ biosynthesis has emerged as a crucial axis that influences aging and tissue regeneration. Wnt signaling, a key regulator of cellular proliferation, differentiation, and tissue homeostasis, intersects with NAD⁺ metabolism, a cornerstone of cellular energy balance and genomic stability. This relationship is mediated through shared regulatory pathways involving sirtuins, poly(ADP-ribose) polymerases (PARPs), and metabolic enzymes which are sensitive to cellular NAD⁺ levels. Dysregulation of either pathway is implicated in cancer, age-related decline, and impaired regenerative capacity. This review consolidates current knowledge of the Wnt-NAD⁺ axis and highlights its cooperative roles in maintaining tissue integrity and combating the effects of aging. Furthermore, it explores therapeutic approaches targeting this axis to restore tissue health and enhance the capacity for repair, thereby offering promising avenues for addressing age-associated pathologies.

Visualizing RNA dynamics with high spatial and temporal resolution is key to understanding their biological function. Fluorescent RNAs (FRs), which are fluorescent protein (FP)-like entities comprising RNA aptamers and their cognate fluorogenic dyes, provide an attractive approach for visualizing RNAs in live cells. In this opinion, we present the current potential of emerging FRs for real-time and multiplexed fluorescence imaging of RNA dynamics at the single molecule level or with super-resolution and provide guidance for the methodological and experimental factors that need to be considered when performing RNA imaging by FRs, thus, increasing their effectiveness. We also provide perspectives and future directions for the development of FRs for advanced RNA imaging.

Phosphoinositide (PIP)-mediated AKT signaling is essential for cellular homeostasis because it orchestrates crucial processes such as metabolism, survival, proliferation, and motility. Dysregulation of this pathway drives various pathologies, particularly cancer. Although cytosolic activation of AKT has been extensively studied, its emerging roles in the nucleus have gained attention over the past decade. The complexities of AKT compartmentalization and associated functional mechanisms remain largely unexplored. At the plasma membrane, AKT activation occurs at specialized microdomains and cell-cell junctions where it influences polarity, adhesion, and migration. In endosomes, PIPs coordinate intracellular trafficking and cytoskeletal organization with AKT signaling. Protein scaffolds refine AKT signal specificity by assembling complexes. In the nucleus, AKT interacts with the p53-PIP signalosome and specific kinases to regulate oncogenesis and chemoresistance. This review explores PIP-driven spatial regulation of AKT across cellular compartments, emphasizing its role in cellular responses and oncogenesis. Understanding AKT compartmentalization mechanisms provides valuable insights into cancer biology and novel therapeutic strategies.

A significant subset of the eukaryotic proteome must localize to multiple cellular compartments, necessitating the emergence of mechanisms to produce protein isoforms with distinct targeting sequences. Ly et al. reveal that alternative start-codon selection during translation initiation is a pervasive mechanism for dual localization of proteins by generating N-terminal isoforms.

N-linked glycosylation in the endoplasmic reticulum (ER), catalyzed by two oligosaccharyltransferase (OST) complexes, has long been viewed as a constitutive post-translational modification. Recent discoveries suggest that OST complexes play a much more plastic and directive role in regulating ER processes. Here, we review this work and focus on one specific mechanism that uses N-glycosylation to regulate the stability of the ER chaperone HSP90B1. This degradative process regulates the cell-surface abundance of multiple signaling receptors that are HSP90B1 clients: toll-like receptors, WNT receptors, and growth factor receptors. This unusual system enables the status of ER-based processes to influence the sensitivity of cells to extracellular signals, with implications for tissue growth and development, inflammation, and immune function.

The endolysosomal system in eukaryotic cells regulates nutrient uptake and maintains the composition of the plasma membrane, among many other functions. In autophagy, it contributes not only to the cellular quality control system to remove damaged organelles, aggregates, and pathogens but also to cellular recycling of amino acids. Transport in the endolysosomal network relies on the correct identity of the involved organelles. Rab GTPases and lipid kinases provide this membrane identity on each organelle, thereby orchestrating the protein machinery for membrane fusion and fission. Dynamic exchange of identity markers provides the basis for adaptations of the endolysosomal system, which is closely linked to cellular nutrient signaling. Here, recent structural and functional insights into the regulation and interplay of Rab regulators, lipid kinases, and tethering complexes are reviewed, focusing on the model organism Saccharomyces cerevisiae.