Control the Host Cell Cycle: Viral Regulation of the Anaphase-Promoting Complex

Abstract

Viruses commonly manipulate cell cycle progression to create cellular conditions that are most beneficial to their replication. To accomplish this feat, viruses often target critical cell cycle regulators in order to have maximal effect with minimal input. One such master regulator is the large, multisubunit E3 ubiquitin ligase anaphase-promoting complex (APC) that targets effector proteins for ubiquitination and proteasome degradation. The APC is essential for cells to progress through anaphase, exit from mitosis, and prevent a premature entry into S phase. These far-reaching effects of the APC on the cell cycle are through its ability to target a number of substrates, including securin, cyclin A, cyclin B, thymidine kinase, geminin, and many others. Recent studies have identified several proteins from a number of viruses that can modulate APC activity by different mechanisms, highlighting the potential of the APC in driving viral replication or pathogenesis. Most notably, human cytomegalovirus (HCMV) protein pUL21a was recently identified to disable the APC via a novel mechanism by targeting APC subunits for degradation, both during virus infection and in isolation. Importantly, HCMV lacking both viral APC regulators is significantly attenuated, demonstrating the impact of the APC on a virus infection. Work in this field will likely lead to novel insights into viral replication and pathogenesis and APC function and identify novel antiviral and anticancer targets. Here we review viral mechanisms to regulate the APC, speculate on their roles during infection, and identify questions to be addressed in future studies.

Human papillomavirus type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by dysregulating EMI1 expression in mitosis

“…Many viruses seem to subvert APC/C activity (Fehr and Yu, 2013; Heilman et al, 2005; Mo et al, 2012). Since ribonucleotide reductase subunit 2 (R2), thymidine kinase 1 (TK) and thymidylate kinase (TMPK) are APC/C CDH1 substrates and required for DNA replication, it has been suggested APC/C inhibition creates a permissive environment for DNA replication of viruses that otherwise do not express these DNA replication factors (Mo et al, 2012).…”

“…In this report, we examine the degradation of a range of different APC/C substrates during mitotic progression and find that HPV16 E7 can be added to an expanding list of viral proteins that manipulate the APC/C (Fehr and Yu, 2013; Heilman et al, 2005; Mo et al, 2012). The SAC-independent APC/C inhibitor, EMI1, is an E2F transcriptional target (Hsu et al, 2002) and is not only transcriptionally upregulated by HPV16 E7, but the EMI1 protein is also stabilized during mitosis.…”

Degrons in cancer

“…These include the K3 and K5 E3 ligases of KSHV, which interfere with antigen presentation (273), and the BPLF1 deubiquitinase of EBV, which enhances the production of infectious particles (274). Viruses may also alter APC/C function through as yet undefined mechanisms with unknown physiological consequences (275).…”

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

“…As with all viruses, HCMV depends on the host cell to provide macromolecular building blocks for virion production, and throughout the course of its evolution, HCMV has adapted to manipulate numerous fundamental cellular processes, including RNA accumulation (4), translation (5), metabolism (6,7), secretory pathways (8), and the cell cycle (9).…”