Nucleus (Austin, Tex.)最新文献

Nuclear trafficking is essential for cellular function and biomedical applications such as nucleus-targeted drug delivery; however, how passive nuclear transport varies across cell types and phenotypic states remains poorly understood. Here, we investigate passive nuclear transport of fluorescent molecular cargoes spanning 500-20,000 Da across multiple cell lines. We observe cell-line-specific nuclear restrictions and find that passive nuclear uptake does not exhibit a monotonic dependence on molecular weight, suggesting non-Fickian transport behavior. Furthermore, transforming a healthy breast cell model into an invasive-like phenotype via TGF-Beta treatment significantly altered passive nuclear transport characteristics, closely resembling those of a well-established invasive breast cancer cell line. These phenotype-dependent changes in nuclear permeability provide new insight into fundamental biophysical alterations associated with cancerous cellular transformation.

Hutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder. It is caused by a point mutation in the LMNA gene leading to the production of the dominant-negative progerin isoform of the nuclear envelope protein lamin A. Most of the mechanistic insights into the disease have come from studies using cellular or mouse models of HGPS. To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, we performed transcriptomic analysis of a comprehensive set of HGPS patients. We find misexpression of several cellular pathways, including multiple signaling pathways, the Unfolded Protein Response (UPR) and mesodermal cell fate specification. Variability amongst individual patients was limited, with misregulation of the major pathways observed in most patients. Comparing the transcriptome of patients with an inducible HGPS cell model, we also identified the primary target pathways of the disease-causing progerin protein.

The immune system functions within tissue microenvironments of mechanical and geometrical constraints. Within these constraints, immune cells must rapidly move and execute effector functions to regulate innate and adaptive immunity. Here, we review the impact of nuclear mechanobiology on immune cell functionality. We define how non-genetic physical properties of the nucleus such as shape, stiffness and deformability are regulated and directly impact immune cell functions ranging from trafficking routes to pathogen killing. We highlight that studying immune cells allowed breakthroughs in understanding how the nucleus acts as a sensor for spatial constraints, as a break or enabler for cell migration, and as an extracellular trap to kill pathogens. Further, we discuss the unknowns of nuclear mechanobiology and consider the impact of chromatin, condensates, and nuclear membrane components. Together, this review provides an overarching framework of the cellular, physical, and immunological principles of nuclear mechanobiology in immune cells.

Nuclear deformation is a central challenge for migration of cells through confined spaces in the tissue interstitium. In this paper, we review studies on the mechanical roles of the nucleus in confined cell migration. We focus on mechanical force generation by the cytoskeleton on the nuclear surface, the properties of sub-nuclear structures in the process, and functional responses of the nucleus in response to mechanical forces, all in the context of confined cell migration. An emerging theme is that the nucleus acts not only as a barrier for confined migration, but also as a mechanoresponsive organelle whose deformation feeds back to modify cell behaviors. Deciphering these complex processes will be key to understanding how cells navigate complex tissues in development, immunity, and cancer.

Condensin complexes are indispensable for mitotic chromosome condensation. In this review, we summarize their structural and functional features, focusing on ATP-dependent loop extrusion and mitotic chromatin folding. We discuss current models of mitotic chromosome formation with an emphasis on the emerging role of condensin in suppressing interphase chromatin contact patterns during mitosis. Additionally, we outline regulatory mechanisms governing condensin activity, including phosphorylation-dependent and -independent regulation of chromatin loading and unloading. Finally, we connect condensin dysfunction to chromosomal instability, cancer, and neurodevelopmental disorders. Our discussions underscore condensin's significance as a genome architect and a key player in disease pathogenesis.

Mechanotransduction mediated by the tension in lipid membranes is a well-established paradigm. This has been studied largely in the context of the plasma membrane, but recent work shows that it applies also to endomembranes, and specifically to the nuclear envelope. Here, we review membrane tension-mediated mechanotransduction at the nuclear envelope by focusing on its two best characterized modes of action: the cytosolic phospholipase A2 (cPLA₂) pathway, and nuclear pore dilation. We discuss the mechanisms involved and their physiological implications. Finally, we discuss how nuclear envelope tension can be controlled and measured, and how its properties enable mechanosensing with different context-dependency than that of the plasma membrane. These properties apply to cPLA₂ and nuclear pore complexes but potentially also to many other mechanosensors yet to be discovered.

Nuclear morphology is increasingly recognized as an integrative indicator of cellular state across diverse physiological and pathological conditions. Beyond storing genetic material, the nucleus also acts as a dynamic sensor responding to mechanical, biochemical, and epigenetic cues. These stimuli reshape nuclear size, architecture, chromatin organization, and envelope integrity providing valuable information about cell cycle progression, differentiation, senescence, and stress responses. Such features offer a scalable and non-invasive approach to assess cell fate. In this review, we position the nuclear envelope as a key sensor of nuclear morphology, outline major triggers of nuclear deformation, discuss the molecular and biophysical processes preserving nuclear integrity and highlight the diversity of nuclear phenotypes with diagnostic and prognostic value. This review provides a comprehensive and critical synthesis of the current knowledge on the regulation and functional relevance of nuclear morphology to serve as a resource and reference point for future interdisciplinary studies.

Due to its pivotal role as a regulator of nucleocytoplasmic transport, the structure and dynamic gating mechanism of the nuclear pore complex (NPC) is a subject of immense interest. Here, we report key recent advancements discussed at the Selective Transport Control in Biological and Biomimetic Nanopores meeting (Monte Verità, Switzerland, 2024) that gathered NPC experts from a range of disciplines. Novel insights were reported from cutting-edge super-resolution techniques that enable the direct interrogation of the NPC's dynamic central transporter; computational models that unravel the mechanisms of the selective barrier; and synthetic NPC mimics as valuable in vitro models for delineating NPC permeability and transport dynamics. Altogether, three major insights were highlighted: (i) the presence of dynamically organised nuclear transport pathways within the NPC, (ii) the role of nuclear transport receptors that enrich and reinforce the NPC's selective permeability barrier, and (iii) the ability of DNA origami nanostructures to mimic aspects of the NPC with unprecedented precision. Overall, the advancements marked a convergence in our understanding of NPC function by unraveling its dynamic gating mechanism at the nanoscale.

Mechanical forces are a ubiquitous feature of the cellular environment. These forces propagate to the nucleus, where the mechanical response is critical for cellular function and survival. In addition to the nuclear lamina and cytoskeletal connections, chromatin is a key structural and mechanoresponsive element which not only contributes to bulk stiffness but also dynamically adapts its organization in response to mechanical stress. Crucially, chromatin is not a uniform material - its organization and mechanical properties vary across time, cell state, and even within individual nuclei. This heterogeneity underpins compartmentalization, gene regulation, and potentially, disease states when disrupted. In this review, we summarize recent experimental advances that have illuminated chromatin's role in nuclear mechanics, emphasizing the importance of heterogeneity. We argue that an integrated, multiscale, and quantitative framework is essential for dissecting chromatin's mechanical contributions. By doing so, the field will be better positioned to link nuclear mechanics to functional biological outcomes.

The nuclear envelope plays an indispensable role in the spatiotemporal organization of chromatin and transcriptional regulation during the intricate process of cell differentiation. This review outlines the distinct regulatory networks between nuclear envelope proteins, transcription factors and epigenetic modifications in controlling the expression of cell lineage-specific genes during differentiation. Nuclear lamina with its associated nuclear envelope proteins organize heterochromatin via Lamina-Associated Domains (LADs), proximal to the nuclear periphery. Since nuclear lamina is mechanosensitive, we critically examine the impact of extracellular forces on differentiation outcomes. The nuclear envelope is spanned by nuclear pore complexes which, in addition to their central role in transport, are associated with chromatin organization. Furthermore, mutations in the nuclear envelope proteins disrupt differentiation, resulting in developmental disorders. Investigating the underlying nuclear envelope controlled regulatory mechanisms of chromatin remodelling during lineage commitment will accelerate our fundamental understanding of developmental biology and regenerative medicine.