Trends in Cell Biology最新文献

Various mechanisms act in a coordinated manner to maintain proteostasis in different cellular organelles. Nevertheless, with aging, certain proteins escape proteostasis surveillance, misfold, and aggregate. This process can lead to neurodegeneration. Despite the cellular nature of proteostasis, it is regulated by intertissue communication. How these intertissue signaling mechanisms coordinate proteostasis across the organism is largely obscure. Recent studies unveiled that the transforming growth factor (TGF)-β signaling cascade is an organismal proteostasis regulator. Here, we focus on the known roles of the TGF-β pathway as a coordinator of proteostasis and describe the messengers and biological activities that are controlled by this pathway. We also discuss open questions and highlight the potential clinical relevance of these discoveries.

Metalloproteinases (MPs) are crucial for development and homeostasis due to their diverse physiological functions, from the cellular to the organismal level. Their activity is tightly regulated at multiple levels, including epigenetic regulation through DNA methylation and histone modifications. Aberrant MP expression can result in pathological events, involving extracellular matrix remodeling, which can facilitate cancer cell invasion and dissemination. As clinical testing of MP inhibitors has been limited by toxicity, alternative approaches are needed. Epigenetically-driven MP expression is often specific to cancer cells, giving an enticing possibility for cancer cell-specific targeting. Moreover, aberrant epigenetic activity can also drive other metastatic events. Therefore, targeting the epigenetic regulators of MP expression may be a promising alternative approach for the prevention and treatment of metastatic disease.

The generation of blood cells during embryonic development involves a process resembling lineage reprogramming, where specialized cells within the vasculature become blood forming, or hemogenic. These hemogenic cells undergo rapid transcriptional and morphological changes as they appear to switch from an endothelial to blood identity. What controls this process and the exact nature of the hemogenic cells remains debated, with evidence supporting several hypotheses. In this opinion, we synthesize current knowledge and propose a model reconciling conflicting observations, integrating evolutionary and mechanistic insights into blood cell emergence.

Gasdermin D (GSDMD) has garnered significant attention primarily for the pore-forming role of its p30 N-terminal fragment (NT-p30) generated during pyroptosis, a proinflammatory form of cell death. However, emerging evidence suggests that the formation of GSDMD-NT pores is reversible, and the activation of GSDMD does not necessarily lead to pyroptosis. Instead, this process may take part either in other forms of cell death, or in various state changes of living cells, including (i) inflammation regulation, (ii) endolysosomal pathway rewiring, (iii) granule exocytosis, (iv) type II immunity, (v) food tolerance maintenance, and (vi) temporary permeability alteration. This review explores the latest insights into the involvement of GSDMD in cell death and homeostasis maintenance, aiming to underscore the pleiotropic nature of GSDMD.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dire prognosis. Standard-of-care chemotherapy regimens offer marginal survival benefit and carry risk of severe toxicity, while immunotherapy approaches have uniformly failed in clinical trials. Extensive desmoplasia in the PDAC tumor microenvironment (TME) disrupts blood flow to and from the tumor, thereby creating a nutrient-depleted, hypoxic, and acidic milieu that suppresses the function of antitumor immune cells and imparts chemotherapy resistance. Additionally, recent seminal studies have demonstrated crucial roles for metabolic crosstalk - the exchange of metabolites between PDAC cells and stromal cell populations in the TME - in establishing and maintaining core malignant behaviors of PDAC: tumor growth, metastasis, immune evasion, and therapy resistance. In this review, we provide a conceptual overview of metabolic crosstalk and how it evolves under various selection pressures in the TME, analyze the landscape of proposed tumorigenic metabolic crosstalk pathways, and highlight potentially druggable nodes.

Megakaryocytes (MKs) release platelets through a terminal event that results in the complete consumption of their cytoplasm. Once viewed as end-stage conductors of platelet biogenesis, MKs are now recognized as multifunctional regulators of the bone-marrow (BM) niche, supporting hematopoietic stem cell (HSC) maintenance, immune regulation, and extracellular matrix (ECM) remodeling. This multiple identity raises a fundamental question: how is MK homeostasis orchestrated to preserve a functional BM MK pool despite consumptive platelet production? Herein we review recent mechanistic insights into the biology of diverse MK functions, MK lineage development, and homeostatic regulation of megakaryopoiesis. Beyond classical systemic regulation, which maintains platelet counts within a physiological range by sensing the circulating platelet pool, we highlight BM tissue-level homeostatic circuits that treat the MK itself as the primary regulated variable.

Pericentromeric sequences are characterized by their tandem repeat structure, heterochromatinization, and rapid evolution. The rapid evolvement creates highly diversified pericentromeric sequences, which facilitate reproductive isolation, as best exemplified in Drosophila studies. Despite their high variability, pericentromeric sequences ranging from fission yeast to humans are heterochromatinized with the same histone modification, H3K9 methylation. These features present a paradox, how highly variable sequences get recognized by conserved machineries. This Opinion discusses how this paradox is resolved and how diversification and conservation get unified at pericentromeric sequences.

The plasma membrane (PM) of eukaryotic cells is constantly exposed to many challenges that can cause wounds that necessitate rapid and efficient repair mechanisms to ensure cell survival. PM wound repair not only encompasses the immediate resealing of the membrane barrier, which involves exocytosis of internal vesicles to deliver membrane, but also subsequent processes that are essential to restore cellular homeostasis. These include restoration of membrane and cortical cytoskeleton structures, as well as replenishment of intracellular organelles consumed during resealing. Recent evidence suggests that the different steps in PM repair, resealing, restructuring, and restoration, are spatiotemporally correlated and regulated by membrane tension. Recent advances in understanding the different phases of PM repair are reviewed and a time-dependent classification of repair mechanisms is proposed.

Nutrient sensors serve as sentinels of cellular energy status, relaying metabolic information to effectors that reprogram gene expression. Zhou et al. identified an AMP-activated protein kinase (AMPK)-NUP50 axis through which AMPK stabilizes the nucleoporin NUP50 to activate transcriptional programs promoting lipid catabolism and longevity. This redefines the nuclear pore complex (NPC) as a dynamic hormetic effector coupling energy sensing to transcriptional control.

Mitochondria are organelles that are essential for their multiple roles in cell biology, including energy metabolism. Accumulating evidence has revealed that intercellular mitochondrial transfer occurs within the tumor microenvironment (TME). The mitochondrial transfer among the TME components can profoundly affect tumor progression, immune surveillance, and stromal remodeling. Importantly, cancer cells function not only as recipients but also as donors of mitochondria, underscoring the bidirectional nature of this process. This review summarizes the multifaceted roles of mitochondria in cancer cells, immune cells, and stromal cells, with particular emphasis on emerging insights into mitochondrial transfer. In addition, the current implications of mitochondria-targeting therapies and future challenges in this evolving field are highlighted.