Limits...
Membrane lysis during biological membrane fusion: collateral damage by misregulated fusion machines.

Engel A, Walter P - J. Cell Biol. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Models for lipid rearrangements leading to the formation of a fusion pore. The left pathway depicts the classical model for membrane fusion via rupture of a hemifusion diaphragm. Membranes are brought into close apposition (1), the two cis leaflets (blue) fuse to form a hemifusion stalk (2), the stalk expands forming a hemifusion diaphragm in which trans leaflets (green) are in contact (3), and rupture of the hemifusion diaphragm results in a fusion pore (4). In contrast to the classical model for membrane fusion, an alternative pathway, via intermediates drawn on the right, does not always maintain compartmental identity. Formation of a hemifusion stalk results in the nucleation of holes adjacent to the stalk (3a and 3b), which encircles the holes to form a fusion pore.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC2568015&req=5

fig1: Models for lipid rearrangements leading to the formation of a fusion pore. The left pathway depicts the classical model for membrane fusion via rupture of a hemifusion diaphragm. Membranes are brought into close apposition (1), the two cis leaflets (blue) fuse to form a hemifusion stalk (2), the stalk expands forming a hemifusion diaphragm in which trans leaflets (green) are in contact (3), and rupture of the hemifusion diaphragm results in a fusion pore (4). In contrast to the classical model for membrane fusion, an alternative pathway, via intermediates drawn on the right, does not always maintain compartmental identity. Formation of a hemifusion stalk results in the nucleation of holes adjacent to the stalk (3a and 3b), which encircles the holes to form a fusion pore.

Mentions: Membrane fusion is a ubiquitous process in biology that allows for delivery, mixing, and sorting of soluble and membrane integrated macromolecules across membrane barriers. Despite enormous diversity of fusion reactions, the job description components catalyzing membrane fusion remain simple: tether, destabilize, and fuse membranes without allowing contents leakage across the bilayer (Jahn et al., 2003; Sollner, 2004; Wickner and Schekman, 2008). In the prevailing model of membrane fusion, the catalyst that drives the coalescence of juxtaposed bilayers, termed a fusase, initiates the formation of a hemifusion stalk, a nonbilayer intermediate that joins the apposed leaflets of the fusing membranes (Fig. 1, stage 2) (Chernomordik and Kozlov, 2008). Axial expansion of the stalk leads to a single bilayer consisting of the other two leaflets—termed a hemifusion diaphragm—that separates the two compartments (stage 3). Rupture of the hemifusion diaphragm results in a fusion pore (stage 4). At no point in this process are the contents of the two fusing membrane exposed to the environment between the membranes; thus, compartmental identity is preserved. This characteristic of the fusion process is considered vital to biological membrane fusion because leakiness in the fusion pathway could have disastrous consequences for the cell. Depending on their longevity and degree of occlusion, uncontained membrane holes would allow the dissipation of ion gradients, the escape of potentially harmful hydrolases from intracellular compartments, and cell lysis if plasma membranes were compromised during cell–cell or cell–virus fusion events. Thus, it comes as a surprise that recent work has shown that vacuole fusion and yeast mating are prone to lysis when the balance of fusion players is altered (Jin et al., 2004; Aguilar et al., 2007; Starai et al., 2007), and some reports suggest that viral fusases may also cause membrane holes (Shangguan et al., 1996; Blumenthal and Morris, 1999; Frolov et al., 2003). Here we review those perturbations that cause fusases to make holes instead of nonleaky fusion pores and discuss how fusase organization and hypothetical fidelity factors could promote formation of fusion pores over membrane lysis.


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

Engel A, Walter P - J. Cell Biol. (2008)

Models for lipid rearrangements leading to the formation of a fusion pore. The left pathway depicts the classical model for membrane fusion via rupture of a hemifusion diaphragm. Membranes are brought into close apposition (1), the two cis leaflets (blue) fuse to form a hemifusion stalk (2), the stalk expands forming a hemifusion diaphragm in which trans leaflets (green) are in contact (3), and rupture of the hemifusion diaphragm results in a fusion pore (4). In contrast to the classical model for membrane fusion, an alternative pathway, via intermediates drawn on the right, does not always maintain compartmental identity. Formation of a hemifusion stalk results in the nucleation of holes adjacent to the stalk (3a and 3b), which encircles the holes to form a fusion pore.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2568015&req=5

fig1: Models for lipid rearrangements leading to the formation of a fusion pore. The left pathway depicts the classical model for membrane fusion via rupture of a hemifusion diaphragm. Membranes are brought into close apposition (1), the two cis leaflets (blue) fuse to form a hemifusion stalk (2), the stalk expands forming a hemifusion diaphragm in which trans leaflets (green) are in contact (3), and rupture of the hemifusion diaphragm results in a fusion pore (4). In contrast to the classical model for membrane fusion, an alternative pathway, via intermediates drawn on the right, does not always maintain compartmental identity. Formation of a hemifusion stalk results in the nucleation of holes adjacent to the stalk (3a and 3b), which encircles the holes to form a fusion pore.
Mentions: Membrane fusion is a ubiquitous process in biology that allows for delivery, mixing, and sorting of soluble and membrane integrated macromolecules across membrane barriers. Despite enormous diversity of fusion reactions, the job description components catalyzing membrane fusion remain simple: tether, destabilize, and fuse membranes without allowing contents leakage across the bilayer (Jahn et al., 2003; Sollner, 2004; Wickner and Schekman, 2008). In the prevailing model of membrane fusion, the catalyst that drives the coalescence of juxtaposed bilayers, termed a fusase, initiates the formation of a hemifusion stalk, a nonbilayer intermediate that joins the apposed leaflets of the fusing membranes (Fig. 1, stage 2) (Chernomordik and Kozlov, 2008). Axial expansion of the stalk leads to a single bilayer consisting of the other two leaflets—termed a hemifusion diaphragm—that separates the two compartments (stage 3). Rupture of the hemifusion diaphragm results in a fusion pore (stage 4). At no point in this process are the contents of the two fusing membrane exposed to the environment between the membranes; thus, compartmental identity is preserved. This characteristic of the fusion process is considered vital to biological membrane fusion because leakiness in the fusion pathway could have disastrous consequences for the cell. Depending on their longevity and degree of occlusion, uncontained membrane holes would allow the dissipation of ion gradients, the escape of potentially harmful hydrolases from intracellular compartments, and cell lysis if plasma membranes were compromised during cell–cell or cell–virus fusion events. Thus, it comes as a surprise that recent work has shown that vacuole fusion and yeast mating are prone to lysis when the balance of fusion players is altered (Jin et al., 2004; Aguilar et al., 2007; Starai et al., 2007), and some reports suggest that viral fusases may also cause membrane holes (Shangguan et al., 1996; Blumenthal and Morris, 1999; Frolov et al., 2003). Here we review those perturbations that cause fusases to make holes instead of nonleaky fusion pores and discuss how fusase organization and hypothetical fidelity factors could promote formation of fusion pores over membrane lysis.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus