Abstract
Nipah virus (NiV) is a recently emerged and highly pathogenic paramyxovirus that causes a systemic infection in animals and humans and can infect a wide range of cultured cells. Interestingly, the NiV fusion (F) protein has a single arginine at the cleavage site similar to paramyxoviruses that are activated by exogenous trypsin-like enzymes only present in specific cells and tissues and therefore only cause localized infections. We show here that NiV F activation is not mediated by an exogenous serum protease but by an endogenous ubiquitous cellular protease after endocytosis of the protein. In addition to endocytosis, acidification of the endosome is a prerequisite for F cleavage. These results show that activation of the NiV F protein depends on a type of proteolytic cleavage that is clearly different from what is known for other paramyxoviral and orthomyxoviral fusion proteins. To our knowledge, this is the first example of a viral class I fusion protein whose activation depends on clathrin-mediated constitutive endocytosis.
Highlights
Nipah virus (NiV),1 a highly pathogenic paramyxovirus, was isolated in 1999 after an outbreak of fatal encephalitis among pig farmers in Malaysia and Singapore [1]
To determine whether the ubiquitous activation is mediated by a host cell protease or by an exogenous serum protease, cleavage and fusion activity of the NiV F protein was analyzed in the absence of fetal calf serum (FCS)
Class I fusion proteins, which are present in paramyxoviruses, orthomyxoviruses, filoviruses, and retroviruses, are proteolytically processed at basic cleavage sites either in the trans-Golgi network (TGN) by ubiquitous furin-like proteases or after arrival at the cell surface by exogenous trypsin-like proteases [9]
Summary
NiV, Nipah virus; F, fusion; MDCK, Madin-Darby canine kidney; FCS, fetal calf serum; DMEM, DulbeccoЈs modified minimal essential medium; MV, measles virus; Tfn-TR, transferrin-tetramethylrhodamine; TGN, trans-Golgi network. The NiV F protein has a single arginine at the cleavage site (Fig. 1), NiV infection is not restricted to the respiratory tract and does not require exogenous trypsin for its growth in cell culture [5, 7, 13] This suggests that activation of the NiV F protein differs from what is known for other paramyxoviral and orthomyxoviral fusion proteins. Supporting this view, we have shown recently that the NiV F protein is cleaved in all cell lines tested This ubiquitous activation does not require a basic residue at the cleavage site and is, not mediated by a member of the trypsin- or furin-like protease families known to activate other paramyxoviruses [8]
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