A fusion mechanism is any mechanism by which cell fusion or virus–cell fusion takes place, as well as the machinery that facilitates these processes. Cell fusion is the formation of a hybrid cell from two separate cells. There are three major actions taken in both virus–cell fusion and cell–cell fusion: the dehydration of polar head groups, the promotion of a hemifusion stalk, and the opening and expansion of pores between fusing cells. Virus–cell fusions occur during infections of several viruses that are health concerns relevant today. Some of these include HIV, Ebola, and influenza. For example, HIV infects by fusing with the membranes of immune system cells. In order for HIV to fuse with a cell, it must be able to bind to the receptors CD4, CCR5, and CXCR4. Cell fusion also occurs in a multitude of mammalian cells including gametes and myoblasts.
Viral mechanisms
Fusogens
Proteins that allow viral or cell membranes to overcome barriers to fusion are called fusogens. Fusogens involved in virus-to-cell fusion mechanisms were the first of these proteins to be discovered. Viral fusion proteins are necessary for membrane fusion to take place. There is evidence that ancestral species of mammals may have incorporated these same proteins into their own cells as a result of infection. For this reason, similar mechanisms and machinery are utilized in cell–cell fusion.
In response to certain stimuli, such as low pH or binding to cellular receptors, these fusogens will change conformation. The conformation change allows the exposure of hydrophobic regions of the fusogens that would normally be hidden internally due to energetically unfavorable interactions with the cytosol or extracellular fluid. These hydrophobic regions are known as fusion peptides or fusion loops, and they are responsible for causing localized membrane instability and fusion. Scientists have found the following four classes of fusogens to be involved with virus–cell or cell–cell fusions.
Class I fusogens
These fusogens are trimeric, meaning they are made of three subunits. Their fusion loops are hidden internally at the junctions of the monomers before fusion takes place. Once fusion is complete, they refold into a different trimeric structure than the structure they had before fusion. These fusogens are characterized by a group of six α-helices in their post-fusion structure. This class of fusogens contains some of the proteins utilized by influenza, HIV, coronaviruses, and Ebola during infection. This class of fusogens also includes syncytins, which are utilized in mammalian cell fusions.
Class II fusogens
Class II fusogens contain multiple β-pleated sheets. These proteins are also trimeric and take part in the insertion of fusion loops into the target membrane. Their conformation changes can be triggered by exposure to acidic environments. Class II fusogens have a structure distinct from Class I fusogens, but similarly lower the energy barrier for membrane fusion. Class I fusogens are involved in flaviviruses (tick-borne encephalitis); alphaviruses (Semliki Forest virus, Sindbis virus, chikungunya and rubella); and phleboviruses (Rift Valley fever virus and Uukuniemi virus).
Class III fusogens
Class III fusogens are involved with virus–cell fusions. Much like fusogens in the previous two classes, these proteins are trimeric. However, they contain both α-helices and β-pleated sheets. During cell fusion the monomers of these proteins will dissociate but will return to a different trimeric structure after the fusion is complete. They are also involved in the insertion of fusion loops in the membrane.
Class IV fusogens
These reoviral cell–cell fusogens contain fusion loops that can induce cell fusion. They form polymeric structures to induce fusion of membranes. Reoviruses do not have membranes themselves, so class IV fusogens are not usually involved in traditional virus–cell fusion. However, when they are expressed on the surface of cells, they can induce cell–cell fusion.