Cell‐Specific Inhibition of Paramyxovirus Maturation by Proteasome Inhibitors

Abstract

Effects of proteasome inhibitors on the replication of a paramyxovirus in comparison with the effects on replication of an orthomyxovirus and rhabdovirus were investigated. Treatment of Sendai virus (SeV)‐infected LLC‐MK2 cells with 50 μM MG132 reduced virus growth to ca. 1/10,000, and treatment with different concentrations of MG132 reduced virus growth in a dose‐dependent manner. Released amounts of viral proteins were reduced in correspondence with decrease in infectivity. The inhibition of virus maturation was confirmed by an SeV‐like particle formation system. Lactacystin also impaired SeV growth and zLL impaired the growth to a lesser extent, suggesting involvement of proteasomes in the restriction of virus growth. In the presence of MG132, localizations of the M protein and viral F and HN glycoproteins on the cell membrane appeared to be partly dissociated, although the viral glycoproteins were normally transported to the cell surface. These results suggest that an early step of SeV assembly was disturbed by proteasome inhibitors. The relationship of the results with ubiquitin is also discussed. SeV maturation was less susceptible and resistant to MG132 in CV1 cells and A549 cells, respectively, indicating cell specificity of the drug effect. Release of vesicular stomatitis virus also showed high susceptibility to MG132 and release of influenza virus A/WSN/33 was only mildly susceptible to the drug in LLC‐MK2 cells. Effects of proteasome inhibitors on virus maturation are thus highly cell‐specific and partly virus‐specific.

A Leucine Residue in the C Terminus of Human Parainfluenza Virus Type 3 Matrix Protein Is Essential for Efficient Virus-Like Particle and Virion Release

“…8). This finding is consistent with several studies that suggested that ubiquitin is involved in viral budding: (i) proteasome inhibitor treatments block the budding of paramyxoviruses, including PIV5, NiV, and SeV (26,31,58); (ii) potential ubiquitination of the MeV M protein has been observed in cells expressing the M protein together with HA-Ub (38); and (iii) ESCRT factors such as ALIX can bind to ubiquitin and enhance viral budding (59,60).…”

NSs Protein of Rift Valley Fever Virus Induces the Specific Degradation of the Double-Stranded RNA-Dependent Protein Kinase

“…To test whether this degradation system could be involved, we treated cells with specific inhibitors and monitored the effect of NSs on PKR. Inhibition of the proteasomal system by MG132 had a negative effect on RVFV growth, similar to what was observed for other RNA viruses (29,49,67). Nonetheless, dose-response experiments using different concentrations show that MG132 partly restored PKR levels in RVFV-infected cells (Fig.…”

Ubiquitin-independent proteasomal degradation during oncogenic viral infections

“…Therefore, one might suspect that specifically inhibiting the ubiquitin-independent proteasomal degradation events that appear to preferentially target cellular tumor suppressors and viral oncogenes could approach the therapeutic effect of complete proteasome inhibition without invoking as many deleterious side effects. As many viruses are inhibited in vitro by proteasome inhibitors [161-165], curtailing ubiquitin-independent degradation events certainly has therapeutic potential for viral infections. Because PA28γ plays a conspicuous role in many ubiquitin-independent degradation events, modalities that inhibit its expression, function, or prevent it from associating with the 20S CP could provide therapeutically relevant inhibition.…”