Viral inhibition of the anaphase promoting complex enhances replication by elevating nucleotide pools

Abstract

The anaphase promoting complex/cyclosome (APC/C) is a large, ubiquitin ligase and a central regulator of cell cycle progression. By targeting key substrates for degradation during mitosis and G1 phase, the APC/C coordinates metabolic fluctuations that occur during the cell cycle. A diverse range of viruses have convergently evolved mechanisms to bind and inhibit the APC/C; however, a molecular understanding for these interactions has never been demonstrated. Here, we use chicken anemia virus (CAV), a small single-stranded DNA virus encoding only three proteins, to demonstrate the importance of viral APC/C inhibition during replication. We show that the Vp3 protein of CAV inhibits the APC/C, causing a dramatic mitotic arrest during infection. Mutant virus lacking Vp3 are defective for replication and can be rescued by APC/C inhibition. Metabolomic profiling during CAV infection revealed that Vp3 expression mediates a broad increase in nucleotide pools. Moreover, viral inhibition of the APC/C resulted in stabilization of enzymes required for nucleotide biosynthesis. These findings suggest that the APC/C is a general target of many viruses to elevate nucleotide levels and facilitate viral genome replication. Author SummaryViruses dramatically reshape the cells they infect in order to replicate. To do this efficiently, many viruses disrupt the hosts normal control systems, particularly those that regulate cell growth and division. One such system is the anaphase promoting complex/cyclosome (APC/C), a key cellular machine that controls when specific proteins are broken down during the cell cycle. Surprisingly, a wide range of viruses--including adenovirus, HIV, human papillomavirus, herpesvirus, and others--have been shown to interfere with the APC/C. Until now, however, it was unclear why so many unrelated viruses target this same pathway. In our study, we used chicken anemia virus (CAV), one of the smallest known animal viruses, as a simple model to uncover the underlying mechanism. CAV produces just three proteins, one of which--called VP3--strongly inhibits the APC/C. We found that this inhibition increases the availability of nucleotides, the basic building blocks needed to copy viral DNA. By disrupting normal cell cycle control, the virus effectively redirects cellular resources toward its own replication. These findings reveal APC/C inhibition as a common and powerful strategy used by diverse viruses, offering new insight into how viruses exploit host cells and highlighting potential targets for future antiviral therapies.