Proteasome inhibition reduces avian reovirus replication and apoptosis induction in cultured cells

Abstract

The interplay between avian reovirus (ARV) replication and apoptosis and proteasome pathway was studied in cultured cells. It is shown that inhibition of the proteasome did not affect viral entry and host cell translation but had influence on ARV replication and ARV-induced apoptosis. Evidence is provided to demonstrate that ubiquitin-proteasome blocked ARV replication at an early step in viral life cycle. However, viral transcription and protein translation were also reduced markedly after addition of proteasome inhibitor MG132. Treatment of BHK-21 cells with the MG132 markedly decreased virus titer as well as prevented virus-induced apoptosis. The expression of ARV proteins sigmaC, sigmaA, and sigmaNS was also reduced markedly, suggesting that suppression of virus replication is due to down-regulation of these ARV proteins by ubiquitin-proteasome system. MG132 was also shown to suppress ARV sigmaC-induced phosphrylation of p53 on serine 46, caspase 3 activities, and DNA fragmentation leading to complete inhibition of ARV-induced apoptosis.

The Orthopoxvirus 68-Kilodalton Ankyrin-Like Protein Is Essential for DNA Replication and Complete Gene Expression of Modified Vaccinia Virus Ankara in Nonpermissive Human and Murine Cells

“…There have also been reports demonstrating that a functional UPS is essential to other viruses. Replication of coxsackievirus B3 was shown to be reduced in HeLa cells treated with proteasome inhibitors, and similar results were obtained for vesicular stomatitis virus (30,38); moreover, avian reovirus protein expression was markedly reduced in BHK-21 cells treated with MG-132 (8). Therefore, the UPS seems to be a cellular mechanism frequently targeted or used by many different viruses.…”

The p17 Nonstructural Protein of Avian Reovirus Triggers Autophagy Enhancing Virus Replication via Activation of Phosphatase and Tensin Deleted on Chromosome 10 (PTEN) and AMP-activated Protein Kinase (AMPK), as well as dsRNA-dependent Protein Kinase (PKR)/eIF2α Signaling Pathways

“…It was proved that p17 plays an important role in regulating cell cycle and host cellular translation but does not induce cellular apoptosis (2)(3)(4). The C protein is encoded by the third ORF of the S1 segment, which is responsible for host cell attachment (5) and induction of apoptosis (2,6). Moreover, after initial binding of C protein to receptor(s) on the cell membrane, ARV enters their host cells using a caveolin-1-mediated and dynamin-2-dependent endocytic pathway that requires activation of p38 and Src signaling pathways (7).…”

Orthopoxviruses Require a Functional Ubiquitin-Proteasome System for Productive Replication

“…Evidence indicates that proteasome inhibitors effectively inhibit viral processes across a variety of virus species, including human immunodeficiency virus (52), human cytomegalovirus (46), herpes simplex virus (13), murine hepatitis virus (72), vesicular stomatitis virus (39), coxsackievirus (55), infectious bursal disease virus (31), and avian reovirus (9). Proteasome inhibitors effectively inhibit viral propagation of these species through a variety of distinct mechanisms.…”