Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.

The Human Cytomegalovirus pUL145 Isoforms Act as Viral DDB1-Cullin-Associated Factors to Instruct Host Protein Degradation to Impede Innate Immunity

“…To instruct the degradation of different host restriction factors, several viruses including HIV-1, HIV-2, HCMV, MCMV, PIV, and HBV take advantage of DDB1 and CRLs (Becker et al, 2019). This raises the interesting question of whether this is simply a coincidence or if these modular E3 ligases are particularly prone to viral exploitation.…”

“…Thus, CRL inhibitory drugs elicit strong anti-proliferative effects and are hence under investigation as potential anti-tumor drugs. As several aspects of the CRL-proteasome system are druggable (Becker et al, 2019), identification of host restriction factors, which are specifically targeted by CRLs in infected cells, may facilitate the discovery of novel drug targets and the development of more specific drugs with lesser side effects.…”

Diverse and pivotal roles of neddylation in metabolism and immunity

“…pUL145 was recently demonstrated to simultaneously interact with STAT2 and CRL4 adaptor DDB1 and thereby targets STAT2 for ubiquitination and degradation by CRL4 [199]. MLN4924 treatment restored STAT2 expression in infected cells and elicited antiviral activity [180,200]. Rotavirus nonstructural protein NSP1 was reported to simultaneously interact with both CUL3 and b-TRCP and thereby assemble CRL3 to target b-TRCP for ubiquitination and subsequent degradation, leading to the inactivation of NF-jB to suppress host antiviral responses [201].…”

Prophylactic and therapeutic HBV vaccination by an HBs-expressing cytomegalovirus vector lacking an interferon antagonist

“…These findings prompted us to evaluate the potential of CMV as platform for prophylactic and therapeutic vaccines against CHB in the established HBV hydrodynamic injection (HDI) mouse model. Our recent findings indicate that the interferon (IFN) antagonism of CMVs relies on viral proteins targeting the transcription factor STAT2 for proteasomal degradation by exploiting the adapter protein DDB1 and cellular Cullin RING ubiquitin ligases(25–27). Virus mutants lacking these immune evasins are replication competent but highly attenuated in vivo (28).…”