Membrane signalosome: Where biophysics meets systems biology

Kandy, Sreeja Kutti; Janmey, Paul A.; Radhakrishnan, Ravi

doi:10.1016/j.coisb.2021.02.001

Cited by 3 publications

(1 citation statement)

References 64 publications

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“…Larger signalosome assemblies, such as T cell receptor microclusters or focal adhesion sites require a minimal size to be functional and able to induce signalling. Typically, they feature sizes in between 10-400 nm (diameter), which is within the range of the membrane area provided by single EVs (Crescitelli et al, 2021;Horzum et al, 2014;Kandy et al, 2021;Yi et al, 2019). The contact area between an EV and a target cell membrane needs to be large enough to allow for receptor-ligand interactions and the formation of a sufficiently large signalosome.…”

Section: Prediction : Single Evs Present Enough Protein Ligands On T...mentioning

confidence: 99%

Membranes on the move: The functional role of the extracellular vesicle membrane for contact‐dependent cellular signalling

Jahnke,

Staufer

2024

J of Extracellular Vesicle

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Extracellular vesicles (EVs), lipid‐enclosed structures released by virtually all life forms, have gained significant attention due to their role in intercellular and interorganismal communication. Despite their recognized importance in disease processes and therapeutic applications, fundamental questions about their primary function remain. Here, we propose a different perspective on the primary function of EVs, arguing that they serve as essential elements providing membrane area for long‐distance, contact‐dependent cellular communication based on protein‐protein interaction. While EVs have been recognized as carriers of genetic information, additional unique advantages that they could provide for cellular communication remain unclear. Here, we introduce the concept that the substantial membrane area provided by EVs allows for membrane contact‐dependent interactions that could be central to their function. This membrane area enables the lateral diffusion and sorting of membrane ligands like proteins, polysaccharides or lipids in two dimensions, promoting avidity‐driven effects and assembly of co‐stimulatory architectures at the EV‐cell interface. The concept of vesicle‐induced receptor sequestration (VIRS), for example, describes how EVs confine and focus receptors at the EV contact site, promoting a dense local concentration of receptors into signalosomes. This process can increase the signalling strength of EV‐presented ligands by 10‐1000‐fold compared to their soluble counterparts. The speculations in this perspective advance our understanding of EV‐biology and have critical implications for EV‐based applications and therapeutics. We suggest a shift in perspective from viewing EVs merely as transporters of relevant nucleic acids and proteins to considering their unique biophysical properties as presentation platforms for long‐distance, contact‐dependent signalling. We therefore highlight the functional role of the EV membrane rather than their content. We further discuss how this signalling mechanism might be exploited by virus‐transformed or cancer cells to enhance immune‐evasive mechanisms.

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Section: Prediction : Single Evs Present Enough Protein Ligands On T...mentioning

confidence: 99%

Membranes on the move: The functional role of the extracellular vesicle membrane for contact‐dependent cellular signalling

Jahnke,

Staufer

2024

J of Extracellular Vesicle

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Cyclophilin A is a ligand for RAGE in thrombo-inflammation

Seizer,

von Ungern-Sternberg,

Haug

et al. 2024

Cardiovascular Research

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Aims Cyclophilin A (CyPA) induces leukocyte recruitment and platelet activation upon release into the extracellular space. Extracellular CyPA therefore plays a critical role in immuno-inflammatory responses in tissue injury and thrombosis upon platelet activation. To date, CD147 (EMMPRIN) has been described as the primary receptor mediating extracellular effects of CyPA in platelets and leukocytes. The receptor for advanced glycation end products (RAGE) shares inflammatory and prothrombotic properties and has also been found to have similar ligands as CD147. In this study, we investigated the role of RAGE as a previously unknown interaction partner for CyPA. Methods and Results Confocal imaging, proximity ligation, co-immunoprecipitation, and atomic force microscopy were performed and demonstrated an interaction of CyPA with RAGE on the cell surface. Static and dynamic cell adhesion and chemotaxis assays towards extracellular CyPA using human leukocytes and leukocytes from RAGE-deficient Ager-/- mice were conducted. Inhibition of RAGE abrogated CyPA-induced effects on leukocyte adhesion and chemotaxis in vitro. Accordingly, Ager-/- mice showed reduced leukocyte recruitment and endothelial adhesion towards CyPA in vivo. In wildtype mice, we observed a downregulation of RAGE on leukocytes when endogenous extracellular CyPA was reduced. We furthermore evaluated the role of RAGE for platelet activation and thrombus formation upon CyPA stimulation. CyPA-induced activation of platelets was found to be dependent on RAGE, as inhibition of RAGE, as well as platelets from Ager-/- mice showed a diminished activation and thrombus formation upon CyPA stimulation. CyPA-induced signaling through RAGE was found to involve central signaling pathways including the adaptor protein MyD88, intracellular Ca2+ signaling, as well as NF-κB activation. Conclusion We propose RAGE as a hitherto unknown receptor for CyPA mediating leukocyte as well as platelet activation. The CyPA-RAGE interaction thus represents a novel mechanism in thrombo-inflammation.

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Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation

Mesa-Herrera

Marín

Torrealba

et al. 2022

Front. Mol. Neurosci.

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There exists considerable interest to unveil preclinical period and prodromal stages of Alzheimer's disease (AD). The mild cognitive impairment (MCI) is characterized by significant memory and/or other cognitive domains impairments, and is often considered the prodromal phase of AD. The cerebrospinal fluid (CSF) levels of β-amyloid (βA), total tau (t-tau), and phosphorylated tau (p-tau) have been used as biomarkers of AD albeit their significance as indicators during early stages of AD remains far from accurate. The new biomarkers are being intensively sought as to allow identification of pathological processes underlying early stages of AD. Fifty-three participants (75.4 ± 8.3 years) were classified in three groups as cognitively normal healthy controls (HC), MCI, and subjective memory complaints (SMC). The subjects were subjected to a battery of neurocognitive tests and underwent lumbar puncture for CSF extraction. The CSF levels of estrogen-receptor (ER)-signalosome proteins, βA, t-tau and p-tau, were submitted to univariate, bivariate, and multivariate statistical analyses. We have found that the components of the ER-signalosome, namely, caveolin-1, flotilin-1, and estrogen receptor alpha (ERα), insulin growth factor-1 receptor β (IGF1Rβ), prion protein (PrP), and plasmalemmal voltage dependent anion channel 1 (VDAC) could be detected in the CSF from all subjects of the HC, MCI, and SMC groups. The six proteins appeared elevated in MCI and slightly increased in SMC subjects compared to HC, suggesting that signalosome proteins undergo very early modifications in nerve cells. Using a multivariate approach, we have found that the combination of ERα, IGF-1Rβ, and VDAC are the main determinants of group segregation with resolution enough to predict the MCI stage. The analyses of bivariate relationships indicated that collinearity of ER-signalosome proteins vary depending on the stage, with some pairs displaying opposed relationships between HC and MCI groups, and the SMC stage showing either no relationships or behaviors similar to either HC or MCI stages. The multinomial logistic regression models of changes in ER-signalosome proteins provide reliable predictive criteria, particularly for the MCI. Notably, most of the statistical analyses revealed no significant relationships or interactions with classical AD biomarkers at either disease stage. Finally, the multivariate functions were highly correlated with outcomes from neurocognitive tests for episodic memory. These results demonstrate that alterations in ER-signalosome might provide useful diagnostic information on preclinical stages of AD, independently from classical biomarkers.

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Membrane signalosome: Where biophysics meets systems biology

Cited by 3 publications

References 64 publications

Membranes on the move: The functional role of the extracellular vesicle membrane for contact‐dependent cellular signalling

Membranes on the move: The functional role of the extracellular vesicle membrane for contact‐dependent cellular signalling

Cyclophilin A is a ligand for RAGE in thrombo-inflammation

Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation

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