scholarly journals Tensin Phosphatase-Like System of Hantavirus Facilitates Membrane Fusion to Disrupt Vascular permeability

2021 ◽  
Author(s):  
wenzhong liu ◽  
hualan li
Keyword(s):  
Membrane Fusion ◽  
Vascular Permeability ◽  
Conformational Transition ◽  
Fusion Pore ◽  
C2 Domain ◽  
Phosphatase Domain ◽  
Endosomal Membrane ◽  
E Protein ◽  
Cell Remodeling ◽  
Endosomal Membranes

Increased vascular permeability is a characteristic of Hantavirus illness, for which there is now no treatment. We employed the domain search method to investigate the Hantavirus protein in this present work. The results indicated that the membrane glycoprotein E protein (containing Gn-Gc) of Hantavirus had lipid phosphatase and C2-like domains. The E protein was a tensin phosphatase-like (PTEN) enzyme that could shuttle in the cytoplasm and cell membrane. In an acidic endosomal environment, Gn dissociates, exposing Gc's autophosphorylation region to complete autophosphorylation and activating the C2 domain. The C2 domain facilitates Gc's conformational transition, which is followed by Gc binding to the endosomal membrane. After being inserted into the endosomal membrane, the phosphatase domain of Gc phosphorylates PI(3,4,5)P3 on the endosomal membrane. Then converted PI(3,4,5)P3 to PI(4,5)P2 . PI(4,5)P2 bound to the N-terminal of Gc, completely anchoring the tetramer-shaped Gc to the endosomal membrane and forming a fusion hole. Then analogous to PTEN, phosphorylation of PI(3,4,5)P3 directly induced the disintegration of Gc tetramer. The enlargement of the fusion pore speeded up the fusion of the viral and endosomal membranes. Through the fusion hole, the virus's intracellular material was swiftly discharged into the cytoplasm. The C2 domain promoted the PKC signaling route during Hantavirus membrane fusion, whereas the phosphatase inhibited the PI3K signaling pathway. E protein's PTEN-like action impaired lipid metabolism and endothelial cell remodeling, increasing blood vessel permeability and resulting in renal and cardiac syndromes. Additionally, E protein inhibited the immune system and Akt-mediated eNOS activation, resulting in a cascade of consequences.

Chapter 2b: The molecular antigenic structure of the TBEV

2020 ◽  
Keyword(s):  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Lipid Membrane ◽  
Cell Entry ◽  
Antigenic Structure ◽  
E Proteins ◽  
Amino Acid Sequence Level ◽  
Endosomal Membrane ◽  
E Protein ◽  
Golgi Network

TBEV-particles are assembled in an immature, noninfectious form in the endoplasmic reticulum by the envelopment of the viral core (containing the viral RNA) by a lipid membrane associated with two viral proteins, prM and E. Immature particles are transported through the cellular exocytic pathway and conformational changes induced by acidic pH in the trans-Golgi network allow the proteolytic cleavage of prM by furin, a cellular protease, resulting in the release of mature and infectious TBE-virions. The E protein controls cell entry by mediating attachment to as yet ill-defined receptors as well as by low-pH-triggered fusion of the viral and endosomal membrane after uptake by receptor-mediated endocytosis. Because of its key functions in cell entry, the E protein is the primary target of virus neutralizing antibodies, which inhibit these functions by different mechanisms. Although all flavivirus E proteins have a similar overall structure, divergence at the amino acid sequence level is up to 60 percent (e.g. between TBE and dengue viruses), and therefore cross-neutralization as well as (some degree of) cross-protection are limited to relatively closely related flaviviruses, such as those constituting the tick-borne encephalitis serocomplex.

scholarly journals Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol

2021 ◽  
Author(s):  
Juan Carlos Polanco ◽  
Gabriel Rhys Hand ◽  
Adam Briner ◽  
Chuanzhou Li ◽  
Jürgen Götz
Keyword(s):  
Critical Role ◽  
Membrane Integrity ◽  
Lysosomal Degradation ◽  
Escape Route ◽  
Cellular Invasion ◽  
Endosomal Membrane ◽  
Late Endosomes ◽  
Endosomal Membranes ◽  
Endosomal Pathway ◽  
Tau Aggregation

AbstractThe microtubule-associated protein tau has a critical role in Alzheimer’s disease and other tauopathies. A proposed pathomechanism in the progression of tauopathies is the trans-synaptic spreading of tau seeds, with a role for exosomes which are secretory nanovesicles generated by late endosomes. Our previous work demonstrated that brain-derived exosomes isolated from tau transgenic rTg4510 mice encapsulate tau seeds with the ability to induce tau aggregation in recipient cells. We had also shown that exosomes can hijack the endosomal pathway to spread through interconnected neurons. Here, we reveal how tau seeds contained within internalized exosomes exploit mechanisms of lysosomal degradation to escape the endosome and induce tau aggregation in the cytosol of HEK293T-derived ‘tau biosensor cells’. We found that the majority of the exosome-containing endosomes fused with lysosomes to form endolysosomes. Exosomes induced their permeabilization, irrespective of the presence of tau seeds, or whether the exosomal preparations originated from mouse brains or HEK293T cells. We also found that permeabilization is a conserved mechanism, operating in both non-neuronal tau biosensor cells and primary neurons. However, permeabilization of endolysosomes only occurred in a small fraction of cells, which supports the notion that permeabilization occurs by a thresholded mechanism. Interestingly, tau aggregation was only induced in cells that exhibited permeabilization, presenting this as an escape route of exosomal tau seeds into the cytosol. Overexpression of RAB7, which is required for the formation of endolysosomes, strongly increased tau aggregation. Conversely, inhibition of lysosomal function with alkalinizing agents, or by knocking-down RAB7, decreased tau aggregation. Together, we conclude that the enzymatic activities of lysosomes permeabilize exosomal and endosomal membranes, thereby facilitating access of exosomal tau seeds to cytosolic tau to induce its aggregation. Our data underscore the importance of endosomal membrane integrity in mechanisms of cellular invasion by misfolded proteins that are resistant to lysosomal degradation.

scholarly journals Role of endosomal membrane lipids and NPC2 in cholesterol transfer and membrane fusion

2010 ◽  
Vol 51 (7) ◽  
pp. 1747-1760 ◽  
Author(s):  
Misbaudeen Abdul-Hammed ◽  
Bernadette Breiden ◽  
Matthew A. Adebayo ◽  
Jonathan O. Babalola ◽  
Günter Schwarzmann ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Membrane Lipids ◽  
Endosomal Membrane

scholarly journals Synaptotagmin Expands Membrane Fusion Pore by Facilitating SNARE-Complex Formation

2011 ◽  
Vol 100 (3) ◽  
pp. 185a
Author(s):  
Jiajie Diao ◽  
Janghyun Yoo ◽  
Han-Ki Lee ◽  
Yoosoo Yang ◽  
Dae-Hyuk Kweon ◽  
...  
Keyword(s):  
Complex Formation ◽  
Membrane Fusion ◽  
Snare Complex ◽  
Fusion Pore ◽  
Snare Complex Formation

scholarly journals Genetic Control of Fusion Pore Expansion in the Epidermis ofCaenorhabditis elegans

2007 ◽  
Vol 18 (4) ◽  
pp. 1153-1166 ◽  
Author(s):  
Tamar Gattegno ◽  
Aditya Mittal ◽  
Clari Valansi ◽  
Ken C.Q. Nguyen ◽  
David H. Hall ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Cell Fusion ◽  
Fusion Pore ◽  
Membrane Domains ◽  
Cell Pair ◽  
C Elegans ◽  
Ultrastructural Studies ◽  
Different Temperatures ◽  
Multiple Cell ◽  
Extensive Information

Developmental cell fusion is found in germlines, muscles, bones, placentae, and stem cells. In Caenorhabditis elegans 300 somatic cells fuse during development. Although there is extensive information on the early intermediates of viral-induced and intracellular membrane fusion, little is known about late stages in membrane fusion. To dissect the pathway of cell fusion in C. elegans embryos, we use genetic and kinetic analyses using live-confocal and electron microscopy. We simultaneously monitor the rates of multiple cell fusions in developing embryos and find kinetically distinct stages of initiation and completion of membrane fusion in the epidermis. The stages of cell fusion are differentially blocked or retarded in eff-1 and idf-1 mutants. We generate kinetic cell fusion maps for embryos grown at different temperatures. Different sides of the same cell differ in their fusogenicity: the left and right membrane domains are fusion-incompetent, whereas the anterior and posterior membrane domains fuse with autonomous kinetics in embryos. All but one cell pair can initiate the formation of the largest syncytium. The first cell fusion does not trigger a wave of orderly fusions in either direction. Ultrastructural studies show that epidermal syncytiogenesis require eff-1 activities to initiate and expand membrane merger.

scholarly journals Membrane lysis during biological membrane fusion: collateral damage by misregulated fusion machines

2008 ◽  
Vol 183 (2) ◽  
pp. 181-186 ◽  
Author(s):  
Alex Engel ◽  
Peter Walter
Keyword(s):  
Membrane Fusion ◽  
Biological Membrane ◽  
Membrane Integrity ◽  
Fusion Pore ◽  
Mechanistic Models ◽  
Collateral Damage ◽  
Vacuole Fusion ◽  
Membrane Lysis

In the canonical model of membrane fusion, the integrity of the fusing membranes is never compromised, preserving the identity of fusing compartments. However, recent molecular simulations provided evidence for a pathway to fusion in which holes in the membrane evolve into a fusion pore. Additionally, two biological membrane fusion models—yeast cell mating and in vitro vacuole fusion—have shown that modifying the composition or altering the relative expression levels of membrane fusion complexes can result in membrane lysis. The convergence of these findings showing membrane integrity loss during biological membrane fusion suggests new mechanistic models for membrane fusion and the role of membrane fusion complexes.

Mechanics of membrane fusion/pore formation

2015 ◽  
Vol 185 ◽  
pp. 109-128 ◽  
Author(s):  
Marc Fuhrmans ◽  
Giovanni Marelli ◽  
Yuliya G. Smirnova ◽  
Marcus Müller
Keyword(s):  
Membrane Fusion ◽  
Pore Formation ◽  
Fusion Pore

scholarly journals Restricted movement of lipid and aqueous dyes through pores formed by influenza hemagglutinin during cell fusion.

1994 ◽  
Vol 127 (6) ◽  
pp. 1885-1894 ◽  
Author(s):  
J Zimmerberg ◽  
R Blumenthal ◽  
D P Sarkar ◽  
M Curran ◽  
S J Morris
Keyword(s):  
Cell Membrane ◽  
Membrane Fusion ◽  
Cell Fusion ◽  
Pore Formation ◽  
Fusion Pore ◽  
Restricted Movement ◽  
Influenza Hemagglutinin ◽  
Simultaneous Measurements ◽  
Cell Membrane Capacitance ◽  
Total Fusion

The fusion of cells by influenza hemagglutinin (HA) is the best characterized example of protein-mediated membrane fusion. In simultaneous measurements of pairs of assays for fusion, we determined the order of detectable events during fusion. Fusion pore formation in HA-triggered cell-cell fusion was first detected by changes in cell membrane capacitance, next by a flux of fluorescent lipid, and finally by flux of aqueous fluorescent dye. Fusion pore conductance increased by small steps. A retardation of lipid and aqueous dyes occurred during fusion pore fluctuations. The flux of aqueous dye depended on the size of the molecule. The lack of movement of aqueous dyes while total fusion pore conductance increased suggests that initial HA-triggered fusion events are characterized by the opening of multiple small pores: the formation of a "sieve".

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