scholarly journals COVID-19: The CaMKII_Like System of S Protein Drives Membrane Fusion and Induces Syncytial Multinucleated Giant Cells

2021 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Cell Membrane ◽  
Infected Cell ◽  
Membrane Fusion ◽  
Calcium Ions ◽  
Giant Cells ◽  
Multinucleated Giant Cells ◽  
S Protein ◽  
Viral Membrane ◽  
Ef Hand ◽  
Contact Position

COVID-19 is a unique disease characterized by extensive pulmonary thrombosis and infected syncytial multinucleated giant cells, relating to extensive tissue damage. The SARS-CoV-2 S protein on the membrane of infected cells can initiate receptor-dependent syncytia formation. To study the membrane fusion on S protein, we adopted structural domain search methods to analyze the structural and non-structural proteins of the SARS-COV-2 virus in this study. The results showed that the surface glycoprotein (S) had conserved domains of CaMKII: CaMKII_AD, CaATP_NAI, DUF4440, EF-hand, Protein kinase, and SnoaL-like. Comparing to SARS-COV and MERS, only the CaATP_NAI of SARS-COV-2 is in the contact position of the viral membrane and cell membrane. We believed that when the EF-hand domain (“YEQYIKWPWYIWLGF”) of S protein bound to calcium ions, S2 protein had CaMKII protein activities. After the S protein fusion peptide was inserted into the infected cell membrane and fixed the S2 protein on the cell membrane, the CaMKII_AD prompted the S2 protein to form HR1-HR2 six-helix bundles. The HR1-HR2 hexamer had three CaATP_NAI domains (“APAICHDGKAHFPRE”) near the viral membrane (contact position), the CaATPase activated by magnesium ions, and released energy through ATP phosphorylation. The CaATPase drove the HR1-HR2 hexamer fold irreversibly toward the viral membrane. Then the CaATP_NAI and CaMKII_AD domains extended to the outside and combined the viral membrane and the cell membrane so that the contact position formed a thin barrel structure. The hydrated calcium ions are gathered in the barrel structure to create a calcium bridge. The release action of water in contact position caused the instability of the double membrane, triggering lipid mixing and fusion of the membrane. CaATPases disassembled the barrel structure, and HR1-HR2 hexamer is fell into the cytoplasm. The viral membrane fused with the cell membrane on a large scale. The cytoplasmic contents of the virus mixed with the cell. The S protein of the infected cell may bind to the ACE2 receptor of another cell (or also an infected cell) and then achieved membrane fusion through a similar principle, forming cell syncytia, includes syncytial multinucleated giant cells. The membrane fusion could disrupt the calcium homeostasis in human body, and increased the risk of coagulation and vascular calcification.

scholarly journals COVID-19: The CaMKII_Like System of S Protein Drives Membrane Fusion and Induces Syncytial Multinucleated Giant Cells

2021 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Cell Membrane ◽  
Infected Cell ◽  
Membrane Fusion ◽  
Calcium Ions ◽  
Giant Cells ◽  
Multinucleated Giant Cells ◽  
S Protein ◽  
Viral Membrane ◽  
Ef Hand ◽  
Contact Position

COVID-19 is a unique disease characterized by extensive pulmonary thrombosis and infected syncytial multinucleated giant cells, relating to extensive tissue damage. The SARS-CoV-2 S protein on the membrane of infected cells can initiate receptor-dependent syncytia formation. To study the membrane fusion on S protein, we adopted structural domain search methods to analyze the structural and non-structural proteins of the SARS-COV-2 virus in this study. The results showed that the surface glycoprotein (S) had conserved domains of CaMKII: CaMKII_AD, CaATP_NAI, DUF4440, EF-hand, Protein kinase, and SnoaL-like. Comparing to SARS-COV and MERS, only the CaATP_NAI of SARS-COV-2 is in the contact position of the viral membrane and cell membrane. We believed that when the EF-hand domain (“YEQYIKWPWYIWLGF”) of S protein bound to calcium ions, S2 protein had CaMKII protein activities. After the S protein fusion peptide was inserted into the infected cell membrane and fixed the S2 protein on the cell membrane, the CaMKII_AD prompted the S2 protein to form HR1-HR2 six-helix bundles. The HR1-HR2 hexamer had three CaATP_NAI domains (“APAICHDGKAHFPRE”) near the viral membrane (contact position), the CaATPase activated by magnesium ions, and released energy through ATP phosphorylation. The CaATPase drove the HR1-HR2 hexamer fold irreversibly toward the viral membrane. Then the CaATP_NAI and CaMKII_AD domains extended to the outside and combined the viral membrane and the cell membrane so that the contact position formed a thin barrel structure. The hydrated calcium ions are gathered in the barrel structure to create a calcium bridge. The release action of water in contact position caused the instability of the double membrane, triggering lipid mixing and fusion of the membrane. CaATPases disassembled the barrel structure, and HR1-HR2 hexamer is fell into the cytoplasm. The viral membrane fused with the cell membrane on a large scale. The cytoplasmic contents of the virus mixed with the cell. The S protein of the infected cell may bind to the ACE2 receptor of another cell (or also an infected cell) and then achieved membrane fusion through a similar principle, forming cell syncytia, includes syncytial multinucleated giant cells. The membrane fusion could disrupt the calcium homeostasis in human body, and increased the risk of coagulation and vascular calcification.

scholarly journals Characterization of the Early Events in Dengue Virus Cell Entry by Biochemical Assays and Single-Virus Tracking

2007 ◽  
Vol 81 (21) ◽  
pp. 12019-12028 ◽  
Author(s):  
Hilde M. van der Schaar ◽  
Michael J. Rust ◽  
Barry-Lee Waarts ◽  
Heidi van der Ende-Metselaar ◽  
Richard J. Kuhn ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Dengue Virus ◽  
Membrane Fusion ◽  
High Ratio ◽  
Cell Entry ◽  
Viral Membrane ◽  
Virus Particles ◽  
Biochemical Assays ◽  
Particle Ratio ◽  
Infectious Unit

ABSTRACT In this study, we investigated the cell entry characteristics of dengue virus (DENV) type 2 strain S1 on mosquito, BHK-15, and BS-C-1 cells. The concentration of virus particles measured by biochemical assays was found to be substantially higher than the number of infectious particles determined by infectivity assays, leading to an infectious unit-to-particle ratio of approximately 1:2,600 to 1:72,000, depending on the specific assays used. In order to explain this high ratio, we investigated the receptor binding and membrane fusion characteristics of single DENV particles in living cells using real-time fluorescence microscopy. For this purpose, DENV was labeled with the lipophilic fluorescent probe DiD (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt). The surface density of the DiD dye in the viral membrane was sufficiently high to largely quench the fluorescence intensity but still allowed clear detection of single virus particles. Fusion of the viral membrane with the cell membrane was evident as fluorescence dequenching. It was observed that DENV binds very inefficiently to the cells used, explaining at least in part the high infectious unit-to-particle ratio. The particles that did bind to the cells showed different types of transport behavior leading to membrane fusion in both the periphery and perinuclear regions of the cell. Membrane fusion was observed in 1 out of 6 bound virus particles, indicating that a substantial fraction of the virus has the capacity to fuse. DiD dequenching was completely inhibited by ammonium chloride, demonstrating that fusion occurs exclusively from within acidic endosomes.

scholarly journals Adipoclast: a multinucleated fat-eating macrophage

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Antoni Olona ◽  
Subhankar Mukhopadhyay ◽  
Charlotte Hateley ◽  
Fernando O. Martinez ◽  
Siamon Gordon ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasma Membrane ◽  
Cell Membrane ◽  
Cell Fusion ◽  
Metabolic Activity ◽  
Current Knowledge ◽  
Giant Cells ◽  
Multinucleated Giant Cells ◽  
Review Current

AbstractCell membrane fusion and multinucleation in macrophages are associated with physiologic homeostasis as well as disease. Osteoclasts are multinucleated macrophages that resorb bone through increased metabolic activity resulting from cell fusion. Fusion of macrophages also generates multinucleated giant cells (MGCs) in white adipose tissue (WAT) of obese individuals. For years, our knowledge of MGCs in WAT has been limited to their description as part of crown-like structures (CLS) surrounding damaged adipocytes. However, recent evidence indicates that these cells can phagocytose oversized lipid remnants, suggesting that, as in osteoclasts, cell fusion and multinucleation are required for specialized catabolic functions. We thus reason that WAT MGCs can be viewed as functionally analogous to osteoclasts and refer to them in this article as adipoclasts. We first review current knowledge on adipoclasts and their described functions. In view of recent advances in single cell genomics, we describe WAT macrophages from a ‘fusion perspective’ and speculate on the ontogeny of adipoclasts. Specifically, we highlight the role of CD9 and TREM2, two plasma membrane markers of lipid-associated macrophages in WAT, which have been previously described as regulators of fusion and multinucleation in osteoclasts and MGCs. Finally, we consider whether strategies aiming to target WAT macrophages can be more selectively directed against adipoclasts.

Trophoblast Cell Membrane Interactions at Implantation

1970 ◽  
Vol 28 ◽  
pp. 310-311
Author(s):  
A. C. Enders
Keyword(s):  
Epithelial Cells ◽  
Cell Membrane ◽  
Membrane Fusion ◽  
Trophoblast Cell ◽  
Membrane Interactions ◽  
Uterine Epithelial Cells ◽  
Functional Complex ◽  
Cytotrophoblast Cells ◽  
Complex Relationships ◽  
Syncytial Trophoblast

The alteration in membrane relationships seen at implantation include 1) interaction between cytotrophoblast cells to form syncytial trophoblast and addition to the syncytium by subsequent fusion of cytotrophoblast cells, 2) formation of a wide variety of functional complex relationships by trophoblast with uterine epithelial cells in the process of invasion of the endometrium, and 3) in the case of the rabbit, fusion of some uterine epithelial cells with the trophoblast.Formation of syncytium is apparently a membrane fusion phenomenon in which rapid confluence of cytoplasm often results in isolation of residual membrane within masses of syncytial trophoblast. Often the last areas of membrane to disappear are those including a desmosome where the cell membranes are apparently held apart from fusion.

CLINICAL AND MORPHOLOGICAL CORRELATIONS AND HISTOPATHOLOGY OF JOINT DAMAGE IN PATIENTS WITH DIFFUSE-TYPE TENOSYNOVIAL GIANT CELL TUMOR

2019 ◽  
Vol 72 (12) ◽  
Author(s):  
Olena O Dyadyk ◽  
Anastasiia Hryhorovska
Keyword(s):  
Giant Cell Tumor ◽  
Giant Cell ◽  
Cell Size ◽  
Giant Cells ◽  
Cell Tumor ◽  
Multinucleated Giant Cells ◽  
Diffuse Type ◽  
Association Coefficient ◽  
Mean Values ◽  
Tenosynovial Giant Cell Tumor

Introduction: Tenosynovial giant cell tumor (TSGCT) (synonym – pigmented villonodular synovitis) – is a rare benign proliferative lesion of the synovial sheath, localized in the joint capsule, bursa or tendon sheath and characterized by locally destructive growth. Depending on the prevalence within the joint elements, the presence of a capsule around the tumor, histophotographic features of cell structure and clinical behavior TSGCT can be divided to localized or diffuse type. The aim of the study was researching of histopathological properties of diffuse-type TSGCT, determine the parameters its morphological indicators and to find out the correlation between these morphological and clinical parameters. Materials and methods: The research material was used biopsy (resect) of pathological lesions from 50 patients who were diagnosed and histologically verified diffuse-type TSGCT. Microscopic examinations of the stained sections and their photo archiving were carried out with use of a Olympus-CX 41 light optical microscope. Group measurable parameters (mean values and Pearson tetrachoric index (association coefficient) were calculated in groups of comparison for morphological and clinical indices of TSGCT. The mean values were compared by Student’s test, P value of ≤0.1 was considered statistically significant. Results:Correlation analysis of indicators that accounted for the pairs of cases «clinic – morphology» revealed the relationships, that had the highest parameters of the association coefficient between such indicators: «presence of villous growths» - «severity of hemosiderosis» (if hypertrophied synovial villi available, with vascular injection and pronounced proliferation of synovial cells, there is also a significant accumulation of hemosiderin pigment); «presence of villous growths» - «type of predominant cellular proliferates» (if cells of TSGCT diffuse type consists of monotonous sheets of stromal cells, with uniform, oval to reniform nuclei, the proliferation of villi in synovial layer is non-distinctive); «presence of nodes» - «kind of stroma» (if nodes predominate, their histological structure is mainly represented by polymorphic clusters of synovitis cells in the form of cells, strands, chains, solid formations, among immature connective tissue with low hyalinosis); «cell size (area, cm²)» - «severity of haemosiderosis» and «cell size (area, cm²)» - «the number of multinucleated giant cells» (there is a pronounced deposition of pigment and accumulation of osteoclast-like multinucleated giant cells type, although usually their number is relatively small compared to the localized type of TSGCT). Conclusions: Morphological parameters, that we have identified, characterize pathological changes in the tissues of TSGCT; careful analysis of the frequency of their occurrence in the different comparison groups made it possible to establish intergroup differences and correlations between individual indicators, which were previously unknown or not obvious. Our study was determine to analyze of incidence rates and correlation relationships, revealed some previously unknown differences and dependencies that are important for understanding the pathogenesis, improvement of diagnosis and prognosis of diffuse-type TSGCT.

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