Abstract:The traditional view of the nuclear envelope (NE) was that it represented a relatively inert physical barrier within the cell, whose main purpose was to separate the nucleoplasm from the cytoplasm. However, recent research suggests that this is far from the case, with new and important cellular functions being attributed to this organelle. In this review we describe research suggesting an important contribution of the NE and its constituents in regulating the functions of cells of the innate and adaptive immun… Show more
“…SMG T RM also expressed stretch-activated InsP3Rs, which are involved in intracellular Ca 2+ release upon nuclear compression (fig. S7E) ( 29 , 63 ). We did not detect noticeable differences between memory T cell subset expression of factors regulating NE structure, including lamin A/C, lamin B receptor, and emerin, as well as members of the linker of nucleoskeleton and cytoskeleton complex Sun1/2 and nesprins 1 to 4 (fig.…”
Tissue-resident CD8
+
T cells (T
RM
) continuously scan peptide-MHC (pMHC) complexes in their organ of residence to intercept microbial invaders. Recent data showed that T
RM
lodged in exocrine glands scan tissue in the absence of any chemoattractant or adhesion receptor signaling, thus bypassing the requirement for canonical migration-promoting factors. The signals eliciting this noncanonical motility and its relevance for organ surveillance have remained unknown. Using mouse models of viral infections, we report that exocrine gland T
RM
autonomously generated front-to-back F-actin flow for locomotion, accompanied by high cortical actomyosin contractility, and leading-edge bleb formation. The distinctive mode of exocrine gland T
RM
locomotion was triggered by sensing physical confinement and was closely correlated with nuclear deformation, which acts as a mechanosensor via an arachidonic acid and Ca
2+
signaling pathway. By contrast, naïve CD8
+
T cells or T
RM
surveilling microbe-exposed epithelial barriers did not show mechanosensing capacity. Inhibition of nuclear mechanosensing disrupted exocrine gland T
RM
scanning and impaired their ability to intercept target cells. These findings indicate that confinement is sufficient to elicit autonomous T cell surveillance in glands with restricted chemokine expression and constitutes a scanning strategy that complements chemosensing-dependent migration.
“…SMG T RM also expressed stretch-activated InsP3Rs, which are involved in intracellular Ca 2+ release upon nuclear compression (fig. S7E) ( 29 , 63 ). We did not detect noticeable differences between memory T cell subset expression of factors regulating NE structure, including lamin A/C, lamin B receptor, and emerin, as well as members of the linker of nucleoskeleton and cytoskeleton complex Sun1/2 and nesprins 1 to 4 (fig.…”
Tissue-resident CD8
+
T cells (T
RM
) continuously scan peptide-MHC (pMHC) complexes in their organ of residence to intercept microbial invaders. Recent data showed that T
RM
lodged in exocrine glands scan tissue in the absence of any chemoattractant or adhesion receptor signaling, thus bypassing the requirement for canonical migration-promoting factors. The signals eliciting this noncanonical motility and its relevance for organ surveillance have remained unknown. Using mouse models of viral infections, we report that exocrine gland T
RM
autonomously generated front-to-back F-actin flow for locomotion, accompanied by high cortical actomyosin contractility, and leading-edge bleb formation. The distinctive mode of exocrine gland T
RM
locomotion was triggered by sensing physical confinement and was closely correlated with nuclear deformation, which acts as a mechanosensor via an arachidonic acid and Ca
2+
signaling pathway. By contrast, naïve CD8
+
T cells or T
RM
surveilling microbe-exposed epithelial barriers did not show mechanosensing capacity. Inhibition of nuclear mechanosensing disrupted exocrine gland T
RM
scanning and impaired their ability to intercept target cells. These findings indicate that confinement is sufficient to elicit autonomous T cell surveillance in glands with restricted chemokine expression and constitutes a scanning strategy that complements chemosensing-dependent migration.
“…Ion channels control the movement of ions, such as Na + , K + , and Ca 2+ , across cell membranes, both plasma and intracellular membranes such as mitochondrial, lysosomal, endoplasmic reticulum membranes and nuclear membranes, and are known to be important cellular sensors and participate in cell signalling cascades in numerous cell types ( Selezneva et al, 2022 ).…”
The expanding roles of macrophages in physiological and pathophysiological mechanisms now include normal tissue homeostasis, tissue repair and regeneration, including neuronal tissue; initiation, progression, and resolution of the inflammatory response and a diverse array of anti-microbial activities. Two hallmarks of macrophage activity which appear to be fundamental to their diverse cellular functionalities are cellular plasticity and phenotypic heterogeneity. Macrophage plasticity allows these cells to take on a broad spectrum of differing cellular phenotypes in response to local and possibly previous encountered environmental signals. Cellular plasticity also contributes to tissue- and stimulus-dependent macrophage heterogeneity, which manifests itself as different macrophage phenotypes being found at different tissue locations and/or after different cell stimuli. Together, plasticity and heterogeneity align macrophage phenotypes to their required local cellular functions and prevent inappropriate activation of the cell, which could lead to pathology. To execute the appropriate function, which must be regulated at the qualitative, quantitative, spatial and temporal levels, macrophages constantly monitor intracellular and extracellular parameters to initiate and control the appropriate cell signaling cascades. The sensors and signaling mechanisms which control macrophages are the focus of a considerable amount of research. Ion channels regulate the flow of ions between cellular membranes and are critical to cell signaling mechanisms in a variety of cellular functions. It is therefore surprising that the role of ion channels in the macrophage biology has been relatively overlooked. In this review we provide a summary of ion channel research in macrophages. We begin by giving a narrative-based explanation of the membrane potential and its importance in cell biology. We then report on research implicating different ion channel families in macrophage functions. Finally, we highlight some areas of ion channel research in macrophages which need to be addressed, future possible developments in this field and therapeutic potential.
“…These pathologies include movement disorders and myopathies (Dauer and Worman 2009 ; Meinke and Schirmer 2016 ), aging-related diseases causing reduced life span and progeria (Kubben and Misteli 2017 ; Fichtman et al 2019 ), lethal defects in the embryo (Turner and Schlieker, 2016 ), and lipodystrophies (Shackleton et al 2000 ). Disruption of NE stability is also common in cancer cells causing DNA damage, cancer-relevant chromosomal rearrangements, and the initiation of pro-inflammatory pathways (Lim et al 2016 ; Umbreit and Pellman 2017 ; Hatch 2018 ; Selezneva et al 2022 ), underscoring the need to unravel its organization and dynamics. Fig.…”
Nucleus is at the center stage of cellular drama orchestrated in the life of a cell and the nucleoplasm is surrounded by a double membranous compartment constituting the Nuclear membrane/envelope (NE) that separates it from the cytoplasm in nucleated cells. The initial understanding of the NE was that of a border security entity between the nucleus and the cytoplasm, separating gene regulation and transcription in the nucleus from translation in the cytoplasm. However, the discovery of a wide array of inherited diseases caused by mutations in genes encoding proteins that reside or interact with NE diverted the interest into deciphering the lipid-protein-rich environment of the NE. Today, the NE is considered a dynamic organelle which forms a functional linkage between the nucleus and the rest of the cell. The exposure of NE to constant mechanical constraints by its connectivity to the large polymer network of the lamina and chromatin on one side, and to the cytoskeleton on the other side results, in a variety of shape changes. We discuss two such deformation, the formation of nuclear blebs and nucleoplasmic reticulum (NER). Although the protein and the lipid composition of NE comprises a small fraction of the total lipid-protein load of the cell, the ability to define the lipid-protein composition of Inner nuclear membrane (INM) and Outer nuclear membrane (ONM) with precision is crucial for obtaining a deeper mechanistic understanding of their lipid-protein interaction and the various signaling pathways that are triggered by them. In addition, this allows us to further understand the direct and indirect roles of NE machinery in the chromosomal organization and gene regulation.
Graphical Abstract
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