Breaking Bad: How Viruses Subvert the Cell Cycle

Abstract

Interactions between the host and viruses during the course of their co-evolution have not only shaped cellular function and the immune system, but also the counter measures employed by viruses. Relatively small genomes and high replication rates allow viruses to accumulate mutations and continuously present the host with new challenges. It is therefore, no surprise that they either escape detection or modulate host physiology, often by redirecting normal cellular pathways to their own advantage. Viruses utilize a diverse array of strategies and molecular targets to subvert host cellular processes, while evading detection. These include cell-cycle regulation, major histocompatibility complex-restricted antigen presentation, intracellular protein transport, apoptosis, cytokine-mediated signaling, and humoral immune responses. Moreover, viruses routinely manipulate the host cell cycle to create a favorable environment for replication, largely by deregulating cell cycle checkpoints. This review focuses on our current understanding of the molecular aspects of cell cycle regulation that are often targeted by viruses. Further study of their interactions should provide fundamental insights into cell cycle regulation and improve our ability to exploit these viruses.

Keywords: cell cycle; checkpoint; degradation; host-pathogen interactions; infection; life cycle; phosphorylation; viruses.

Figure 1

Cell cycle subversion by protein-protein interaction. (A) Binding of Tax and HBx proteins to cyclin and/or CDK promotes cell cycle progression either by enhancing kinase activity and/or weakening the inhibitory effect of CKI (Benn and Schneider, ; Neuveut et al., ; Haller et al., 2002). Direct binding of either K-bZIP protein of KSHV or p30 of HTLV-1 to both CDK2 and cyclin E leads to extended G1 duration or block of G1/S transition (Izumiya et al., ; Baydoun et al., 2010). Similarly, direct interaction of M2 of influenza A virus with cyclin D3 arrested cell cycle in G0/G1 phase (Fan et al., 2017). (Bi) Binding of E1A to p27^KIP1 blocks its inhibition on CDK2 kinase activity, overcoming cell cycle arrest in late G1 phase (Mal et al., 1996). In addition to its association with cyclins, HTLV-1 Tax is also able to interact with p16^INK4A and relieve p16^INK4A-imposed blockage of G1 to S transition (Suzuki et al., ; Low et al., 1997). (Bii) p21^WAF1/CIP1 can block the interaction between Cdc25C and proliferating cell nuclear antigen (PCNA) by competing with Cdc25C for PCNA binding. This observation points to a role of p21^WAF1/CIP1 in G2 cell cycle arrest upon DNA damage (Ando et al., 2001). Competition between core protein of hepatitis C virus and PCNA for the association with p21^WAF1/CIP1 may disrupt PCNA-p21^WAF1/CIP1 binding, leading to impaired cell cycle arrest in G2 and DNA repair in response to damage signals (Wang et al., 2000). (C) E1A protein of adenovirus functions to dissociate E2F-Rb/p107 complexes owing to the interaction of its two conserved regions with Rb (Bagchi et al., ; Raychaudhuri et al., 1991). The release of E2F, therefore, transcriptionally activates various downstream target genes that are required for proliferation and DNA synthesis, including c-myc and cyclin E (Roussel et al., ; Ohtani et al., 1995).

Figure 2

Cell cycle subversion by protein phosphorylation. (A) Direct phosphorylation of Rb by HCMV UL97 protein dissociates E2F-Rb/p107 complexes releasing E2F to activate transcription and cell cycle progression (Hume et al., 2008). HCMV IE1-72 is a viral protein kinase able to directly and selectively phosphorylate transcription factors of the E2F family (E2F1,−2, and−3), leading to E2F-dependent transcriptional activation, thus regulating cell cycle events (Pajovic et al., 1997). (B) Expression of viral S1 gene-encoded σ1s nonstructural protein during reovirus infection leads to G2/M arrest in host cells via σ1s-mediated CDK1 hyperphosphorylation (Poggioli et al., 2000, 2001). Similarly, human herpesvirus 6 (HHV-6)-induces G2/M arrest by increasing the inactive Ser216-phosphorylated form Cdc25C phosphatase that accumulates in the cytoplasm where it has no access to its CDK1 substrate (Li et al., 2011). Members of herpesvirus share the conserved UL24 family of proteins (i.e., UL24, ORF20, and UL76), whose expression induces CDK1 phosphorylation at Tyr15 inhibitory site with ensuing cell cycle G2/M arrest (Nascimento et al., 2009). (C) HSV-1 immediate-early gene product ICP0 triggers a series of phosphorylation events resulting in cytoplasmic sequestration of Cdc25C, which maintains high levels of CDK1 inhibitory phosphorylation, leading to CDK1 inactivation with ensuing G2/M arrest (Li et al., 2008).

Figure 3

Cell cycle subversion by protein degradation. (A) Expression of (Vif) protein of HIV-1 blocks MDM2-mediated proteasomal degradation of p53, by binding to both MDM2 and p53, leading to cell cycle arrest in G2 (Izumi et al., 2010). (B) The degradation of securin by the anaphase promoting complex/cyclosome (APC/C) is essential for the completion of mitosis, leading to correct transmission of chromosomes from mother to daughter cells. The oncoprotein Tax of HTLV-1 is able to promote securin and cyclin B1 degradation, leading to chromosome instability (Liu et al., 2003). (C) ICP0 of HSV-1 possesses an ubiquitin E3 ligase activity (Boutell et al., ; Hagglund et al., 2002), which results in rapid loss of the centromeric protein CENP-C and CENP-A in a proteasome-dependent manner and mitotic block (Everett et al., ; Lomonte et al., 2001). However, it remains unclear whether these two centromere components are direct substrates of the ICP0 E3 ligase (dashed line). Likewise, ICP0 can directly ubiquitinate p53 (Boutell and Everett, 2003), although p53 levels are not reduced during HSV-1 infection (Hobbs and DeLuca, 1999) and, hence, the role of p53 in ICP0-induced perturbation of cell cycle progression remains unclear (dashed line).

Figure 4

Cell cycle subversion by protein redistribution. (A) Nonstructural protein 1 (NS1) of human parvovirus B19 (B19V) leads to G2 arrest, which is mediated by upregulating nuclear localization of repressive E2F4 and E2F5 transcription factors (Wan et al., 2010). (B) Cyclin D3 needs to be imported into the nucleus to assist G0/G1 cell cycle progression (Mahony et al., 1998). Influenza A virus infection perturbs cell cycle progression by redistributing cyclin D3 from the nucleus to the cytoplasm, triggering its proteasomal degradation (Fan et al., 2017). (C) Expression of HIV-1 Vpr induces localized-disruption in the lamin architecture, resulting in G2/M arrest that is dependent on cytoplasmic compartmentalization of Cdc25C, cyclin B1, and Wee1 (Peng et al., ; Laronga et al., ; de Noronha et al., ; Kino et al., 2005).

Figure 5

Cell cycle subversion by virus-encoded homologs of cell cycle regulators. (A) Several gammaherpesviruses encode viral-cyclins (v-cyclin) (Nicholas et al., ; Chang et al., , ; Cesarman et al., ; Li et al., ; Virgin et al., ; Fickenscher and Fleckenstein, 2001) that display strong association with CDK6, leading to the phosphorylation of Rb and histone H1. (Bi) V-cyclin-CDK complexes are significantly more resistant to the inhibition imposed by p21^WAF1/CIP1, p27^KIP1, and p16^INK4A than cyclin D1-CDK complexes in vitro (Swanton et al., 1997). Failure or weak association of p21^WAF1/CIP1 and p27^KIP1 with v-cyclin likely defines the inefficiency of these CKI to inhibit them (Swanton et al., ; Schulze-Gahmen et al., ; Card et al., 2000). (Bii) Higher affinity of v-cyclin for CDK6 than p16^INK4A may prevent its displacement by p16^INK4A. (C) Both crocodile and squirrel poxviruses encode the APC/cyclosome regulator (PACR), which shares sequence similarities to the APC subunit 11 (APC11). PACR mimics the binding ability of APC11 to APC2 but not the ubiquitin ligase activity of APC11. Thus, poxvirus hinders normal cell cycle progression by encoding an inactive homolog of APC11 (Mo et al., 2009).