Prevention of premature fusion activation

Abstract

All viruses have to get their genome across the cell membrane barrier before a productive infection is initiated. Viruses which contain a membrane surrounding the genetic material, overcome this cellular barrier by a fusion of the cellular and viral membrane. These enveloped viruses have developed different strategies to initiate this fusion event, which is performed by the viral fusion proteins. These viral glycoproteins are anchored in the envelope and are triggered by a number of cellular factors. A well established trigger, necessary for fusion and therefore entry of many enveloped viruses, is a low pH environment, found in late endosomes or in lysosomes. The low pH in these acidic endosomal organelles can induce a cascade of conformational changes leading to membrane fusion. During endocytosis, starting at the plasma membrane and ending into lysosomes, the pH is gradually lowered and viruses exploit this acidification to trigger fusion. Fusion enables the virus to escape into the cytoplasm, preventing degradation after fusion with, or maturation into lysosomes. However, a low pH is also found in the late secretory pathway. This could potentially lead to inactivation of the viral fusion proteins through premature activation of irreversible conformational changes, while being transported to the plasma membrane. Viruses have evolved different mechanisms to overcome this problem. Some examples are: proteolytic cleavage, the capability of fusion proteins to reverse between a fusion active and a fusion inactive state and actively controlling the ionic environment. These escape mechanisms of premature activation of many viruses are unclear, for example Rift Valley Fever Virus (RVFV). RVFV causes severe illness in cattle and recently an increase in human cases have also been reported. Understanding the pH escape mechanism of RVFV could lead to the identification of therapeutic targets. To understand possible mechanisms for RVFV premature fusion activation, we will compare the identified fusion mechanisms and their fusion proteins. This will give us more insight in the mechanisms used by enveloped viruses in general and might provide more insight in the mechanism used by RVFV.