Caspase Cleavage of the Nonstructural Protein NS1 Mediates Replication of Aleutian Mink Disease Parvovirus

Abstract

Virus-induced apoptosis of infected cells can limit both the time and the cellular machinery available for virus replication. Hence, many viruses have evolved strategies to specifically inhibit apoptosis. However, Aleutian mink disease parvovirus (ADV) is the first example of a DNA virus that not only induces apoptosis but also utilizes caspase activity to facilitate virus replication. To determine the function of caspase activity during ADV replication, virus-infected cell lysates or purified ADV proteins were incubated with various purified caspases. Caspases cleaved the major nonstructural protein of ADV (NS1) at two caspase recognition sequences, whereas ADV structural proteins could not be cleaved. Importantly, the NS1 products could be identified in ADV-infected cells but were not present in infected cells pretreated with caspase inhibitors. By mutating putative caspase cleavage sites (D to E), we mapped the two cleavage sites to amino acid residues NS1:227 (INTD2S) and NS1:285 (DQTD2S). Replication of ADV containing either of these mutations was reduced 10 3 -to 10 4 -fold compared to that of wild-type virus, and a construct containing both mutations was replication defective. Immunofluorescent studies revealed that cleavage was required for nuclear localization of NS1. The requirement for caspase activity during permissive replication suggests that limitation of caspase activation and apoptosis in vivo may be a novel approach to restricting virus replication.

The New World arenavirus Tacaribe virus induces caspase-dependent apoptosis in infected cells

“…Whether TCRV actively exploits the apoptotic processes to support efficient virus replication and/or release and, if so, by which mechanism, also still need to be determined. A positive influence of apoptosis induction in promoting viral growth or viral replication has been observed for many other viruses (Best et al, 2003;Méndez et al, 2004;Olsen et al, 1996;Wurzer et al, 2003). In those cases apoptotic processes help to overcome the host's immune response or facilitate viral entry or release (Amara & Mercer, 2015;Best et al, 2003;Gliedman et al, 1975;Jeurissen et al, 1992;Teodoro & Branton, 1997).…”

“…A positive influence of apoptosis induction in promoting viral growth or viral replication has been observed for many other viruses (Best et al, 2003;Méndez et al, 2004;Olsen et al, 1996;Wurzer et al, 2003). In those cases apoptotic processes help to overcome the host's immune response or facilitate viral entry or release (Amara & Mercer, 2015;Best et al, 2003;Gliedman et al, 1975;Jeurissen et al, 1992;Teodoro & Branton, 1997). It is therefore tempting to speculate that the need for apoptosis induction during TCRV infection, but not JUNV infection, may be related to previously reported differences in the budding of these two viruses (Groseth et al, 2010;Wolff et al, 2013b), and particularly the proline-rich domain-independent nature of TCRV budding (Urata et al, 2009).…”

“…In contrast, some viruses benefit from cellular apoptosis (Hay & Kannourakis, 2002;Richard & Tulasne, 2012;Roulston et al, 1999;Teodoro & Branton, 1997). For instance, influenza virus, astroviruses and Aleutian mink disease virus all require infection-induced apoptosis for efficient viral replication and release (Best et al, 2003;Méndez et al, 2004;Olsen et al, 1996;Wurzer et al, 2003).…”

Proteolytic Processing and Translation Initiation

“…Cellmediated processing of viral proteins is also frequent, although they tend to be structural components. However, it was recently reported that the caspase-mediated cleavage of the NS1 nonstructural protein of a parvovirus was actually required for a permissive infection, opening the possibility that the cleavage products of such proteins may have distinct and important functions in the cell (51). Intriguingly, with regard to the Cproteins, the NS1 is the primary protein responsible for cell cytotoxicity and may be directly responsible for the induction of apoptosis (52).…”

Infected cell protein 0 encoded by bovine herpesvirus 1 can activate caspase 3 when overexpressed in transfected cells

“…However, there are examples of caspase activation promoting virus replication. For example, caspase cleavage of a nonstructural protein stimulates replication of Aleutian mink disease parvovirus in cultured cells (Best et al, 2003). Caspase 3 can also enhance HSV-1 reactivation from latency when latently infected neurons are explanted (Hunsperger & Wilcox, 2003).…”