Abstract
Nipah virus (NiV) is a BSL-4 classified zoonotic paramyxovirus that causes respiratory or encephalitic diseases. A hallmark of NiV infections, as with all cell infections caused by non-segmented negative-strand RNA viruses, is the formation of cytoplasmic inclusion bodies (IBs). We previously showed that cytosolic NiV IBs, which are formed in infected cells or in cells minimally expressing the NiV nucleocapsid proteins, are associated with the microtubule-organizing center (MTOC) marker γ-tubulin. They also recruit overexpressed cytosolic proteins that are not functionally required for viral replication in IBs and that otherwise might form toxic protein aggregates. Therefore, NiV IBs are thought to share some functional properties with cellular aggresomes. The fact that aggresomes were not found in NiV-infected cells supports the idea that NiV IBs are successfully reducing the proteotoxic stress in infected cells. Only if the proteasome-ubiquitin system is artificially blocked by inhibitors, cellular aggresomes are formed in addition to IBs, but without colocalizing. Although both structures were positive for the classical aggresome markers histone deacetylase 6 (HDAC6) and Bcl-2-associated athanogene 3 (BAG3), they clearly differed in their cellular protein compositions and recruited overexpressed proteins to different extents. The further finding that inhibition of aggresome pathways by HDAC6 or microtubule (MT) inhibitors did neither interfere with IB formation nor with protein sequestration, strengthens the idea that cytosolic NiV IBs can assume some aggresome-like functions without involving active transport processes and canonical cellular aggresome pathways.
Highlights
Nipah virus (NiV) is a biosafety-level 4 (BSL-4) classified paramyxovirus that causes severe respiratory or encephalitic diseases in pigs and humans [1]
The absence of aggresomes in NiV-infected cells at such late time points of infection supports the idea that NiV has evolved alternative mechanisms to limit proteotoxic stress or inhibits aggresome pathways, thereby actively preventing aggresome formation
Because NiV inclusion bodies (IBs) accumulate viral proteins and sequester overexpressed cytosolic proteins, they may serve an additional function in limiting proteotoxic stress during infection
Summary
Nipah virus (NiV) is a biosafety-level 4 (BSL-4) classified paramyxovirus that causes severe respiratory or encephalitic diseases in pigs and humans [1]. The natural reservoir of NiV are Southeast Asian fruit bats, from which the virus is sporadically transmitted to humans, either by direct spillover (NiV-Bangladesh) or via pigs as intermediate hosts (NiV-Malaysia) [1,2,3,4]. In virus particles or infected cells, the viral RNA is encapsidated by the nucleocapsid protein (N), the phosphoprotein (P), and the large viral polymerase (L), which together form the so-called ribonucleoprotein complex (RNP). The M protein links the RNP to the NiV surface glycoproteins and is absolutely essential for the assembly and release of infectious NiV particles [8,9,10]
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