Exosomes are extracellular vesicles that transport different molecules between cells. They are formed and stored inside multivesicular bodies (MVB) until they are released to the extracellular ...environment. MVB fuse along the plasma membrane, driving non‐polarized secretion of exosomes. However, polarized signaling potentially directs MVBs to a specific point in the plasma membrane to mediate a focal delivery of exosomes. MVB polarization occurs across a broad set of cellular situations, e.g. in immune and neuronal synapses, cell migration and in epithelial sheets. In this review, we summarize the current state of the art of polarized MVB docking and the specification of secretory sites at the plasma membrane. The current view is that MVB positioning and subsequent exosome delivery requires a polarizing, cytoskeletal dependent‐trafficking mechanism. In this context, we propose scenarios in which biochemical and mechanical signals could drive the polarized delivery of exosomes in highly polarized cells, such as lymphocytes, neurons and epithelia.
Exosome secretion is a finely tuned mechanism of intercellular communication. Cellular orientation and polarized fusion of multivesicular bodies are central events in this process to enable efficacy and specificity. We offer an integrated perspective of the roles of the different cellular cytoskeletons, small GTPases and phospholipid signaling circuits that drive the polarization of MVBs toward specific points of the plasma membrane and its function in crucial physiological processes including immune and neuronal synapses, cell migration and the function of epithelial sheets.
A new study reveals that non-muscle myosin II plays a central role in the durotaxis of mesenchymal stem cells, with the two major isoforms, II-A and II-B, being cooperatively required for this cell ...movement, and serine phosphorylation of the II-A isoform playing a negative role.
tT cells migrate to lymphoid organs to become activated through specific contacts with antigen-presenting cells bearing foreign antigens. During migration and activation, T lymphocytes are exposed ...not only to diverse biochemical inputs, but also to different mechanical conditions. Passage from the blood or lymph to solid tissues involves lymphocyte rolling, firm arrest and diapedesis through endothelial monolayers. Throughout this process, cells are subjected to diverse fluid flow regimes. After extravasation, T lymphocytes crawl through viscoelastic media of different biochemical and mechanical properties and geometries. In lymph nodes, T cell contact with antigen-presenting cells is guided by rigidity cues and ligand-receptor interactions. T lymphocyte adaptation to diverse mechanical regimes involves multiple signaling and morphological modifications, many of which enable the conversion of mechanical forces into biochemical signals and vice-versa. These components enable T lymphocyte survival, homing and activation. Here, we review the mechanisms that enable T lymphocytes to survive and thrive under the different mechanical conditions they encounter during their life cycle. These processes require the integration of diverse signaling networks that convert extracellular mechano-chemical cues into force, movement and activation.
•Force generation and mechanosensation are interweaved with biochemical signals at every step of T lymphocyte cell cycle.•During extravasation, extracellular forces cooperate with biochemical bonds to promote rolling, firm adhesion and diapedesis.•Integrin activation during extravasation requires intracellular force generation.•T lymphocyte crawling in solid tissues is guided chemically and physically and relies on friction and traction.•Biochemical signals and mechanical responses optimize receptor distribution and cellular outcomes during T cell activation.
Interaction of T cell with antigen-bearing dendritic cells (DC) results in T cell activation, but whether this interaction has physiological consequences on DC function is largely unexplored. Here we ...show that when antigen-bearing DCs contact T cells, DCs initiate anti-pathogenic programs. Signals of this interaction are transmitted from the T cell to the DC, through extracellular vesicles (EV) that contain genomic and mitochondrial DNA, to induce antiviral responses via the cGAS/STING cytosolic DNA-sensing pathway and expression of IRF3-dependent interferon regulated genes. Moreover, EV-treated DCs are more resistant to subsequent viral infections. In summary, our results show that T cells prime DCs through the transfer of exosomal DNA, supporting a specific role for antigen-dependent contacts in conferring protection to DCs against pathogen infection. The reciprocal communication between innate and adaptive immune cells thus allow efficacious responses to unknown threats.
Nonmuscle myosin II (NMII) is a multimeric protein complex that generates most mechanical force in eukaryotic cells. NMII function is controlled at three main levels. The first level includes events ...that trigger conformational changes that extend the complex to enable its assembly into filaments. The second level controls the ATPase activity of the complex and its binding to microfilaments in extended NMII filaments. The third level includes events that modulate the stability and contractility of the filaments. They all work in concert to finely control force generation inside cells. NMII is a common endpoint of mechanochemical signaling pathways that control cellular responses to physical and chemical extracellular cues. Specific phosphorylations modulate NMII activation in a context-dependent manner. A few kinases control these phosphorylations in a spatially, temporally, and lineage-restricted fashion, enabling functional adaptability to the cellular microenvironment. Here, we review mechanisms that control NMII activity in the context of cell migration and division.
The connection between integrins and actin is driving the field of cell migration in new directions. Integrins and actin are coupled through a physical linkage, which provides traction for migration. ...Recent studies show the importance of this linkage in regulating adhesion organization and development. Actin polymerization orchestrates adhesion assembly near the leading edge of a migrating cell, and the dynamic cross-linking of actin filaments promotes adhesion maturation. Breaking the linkage between actin and integrins leads to adhesion disassembly. Recent quantitative studies have revealed points of slippage in the linkage between actin and integrins, showing that it is not always efficient. Regulation of the assembly and organization of adhesions and their linkage to actin relies on signaling pathways that converge on components that control actin polymerization and organization.
Neutrophils destroy invading microorganisms by phagocytosis by bringing them into contact with bactericidal substances, among which ROS are the most important. However, ROS also function as important ...physiological regulators of cellular signaling pathways. Here, we addressed the involvement of oxygen derivatives in the regulation of human neutrophil rolling, an essential component of the inflammatory response. Flow experiments using dihydroethidium‐preloaded human neutrophils showed that these cells initiate an early production of intracellular ROS during the rolling phase of the adhesion cascade, a phenomenon that required cell rolling, and the interaction of the chemokine receptor CXCR2 with their ligand CXCL8. Flow cytometry experiments demonstrated that L‐selectin shedding in neutrophils is triggered by ROS through an autocrine–paracrine mechanism. Preincubation of neutrophils with the NADPH oxidase complex inhibitor diphenyleniodonium chloride significantly increased the number of rolling neutrophils on endothelial cells. Interestingly, the same effect was observed when CXCL8 signaling was interfered using either a blocking monoclonal antibody or an inhibitor of its receptor. These findings indicate that, in response to CXCL8, neutrophils initiate ROS production during the rolling phase of the inflammatory response. This very early ROS production might participate in the modulation of the inflammatory response by inducing L‐selectin shedding in neutrophils.
We propose that activation of the NADPH oxidase complex by CXCL8 releases superoxide anions to the extracellular milieu. This superoxide generates an oxidative attack on the prodomain thiol group of ADAM‐17, which is activated and process the extracellular domain of L‐selectin, causing its release from the cell membrane.
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