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Review
. 2021 Feb 26;13(3):369.
doi: 10.3390/v13030369.

The Role of the Host Ubiquitin System in Promoting Replication of Emergent Viruses

Karl M Valerdi  1 , Adam Hage  1 , Sarah van Tol  1 , Ricardo Rajsbaum  1   2 , Maria I Giraldo  1
Affiliations
Review

The Role of the Host Ubiquitin System in Promoting Replication of Emergent Viruses

Karl M Valerdi et al. Viruses. .

Abstract

Ubiquitination of proteins is a post-translational modification process with many different cellular functions, including protein stability, immune signaling, antiviral functions and virus replication. While ubiquitination of viral proteins can be used by the host as a defense mechanism by destroying the incoming pathogen, viruses have adapted to take advantage of this cellular process. The ubiquitin system can be hijacked by viruses to enhance various steps of the replication cycle and increase pathogenesis. Emerging viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses like Zika and dengue, as well as highly pathogenic viruses like Ebola and Nipah, have the ability to directly use the ubiquitination process to enhance their viral-replication cycle, and evade immune responses. Some of these mechanisms are conserved among different virus families, especially early during virus entry, providing an opportunity to develop broad-spectrum antivirals. Here, we discuss the mechanisms used by emergent viruses to exploit the host ubiquitin system, with the main focus on the role of ubiquitin in enhancing virus replication.

Keywords: Ebola; Nipah; SARS-CoV-2; Zika; antagonism of immune response; emergent viruses; pro-viral function; tripartite motif (TRIM) proteins; ubiquitin system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The ubiquitin system. (A) Free ubiquitin (Ub) is attached to a substrate after a series of ATP-dependent enzymatic reactions involving an E1-activating, E2-conjugating and E3-ligating enzyme. Substrates marked with Ub may be bound for the proteasome for degradation or can have activities altered to promote non-degradative cellular functions. (B) E3 ligases promote Ub transfer differently with RING family members, facilitating the movement of Ub directly from the E2 conjugase to the substrate, while HECT and RBR members first receive Ub from the E2 to their catalytic domain before delivering to the substrate.
Figure 2
Figure 2
The host ubiquitin system can be hijacked by different viruses at different stages of their life cycles. Entry for flaviviruses like Zika virus (ZIKV) can be enhanced by ubiquitination of the envelope protein. The K63-linked ubiquitin ZIKV brings on its envelope protein allows for greater binding affinity to host receptors, improved cellular entry and higher titers. Adenovirus (ADV) hijacks the E3 ubiquitin ligase Mind bomb-1 (Mib1) to facilitate viral genome uncoating and release at the nuclear pore complex (NPC). Ebola virus (EBOV) can hijack TRIM6 to ubiquitinate VP35 to promote its polymerase cofactor activity and enhance viral replication. Egress of EBOV viral-like particles (VLPs) is enhanced by ubiquitination of EBOV VP40 protein by WWP1 (WW Domain Containing E3 Ubiquitin Protein Ligase 1). The influenza A virus (IAV) M2 protein can be ubiquitinated, allowing for better association with M1 and ultimately improved IAV assembly, budding and release of progeny virions.
Figure 3
Figure 3
Viruses can evade immune responses utilizing the ubiquitin system. Viruses have evolved the ability to evade the host-innate immune response by antagonizing IFN production and signaling. SARS-CoV ORF6 can interact with N-Myc to promote its degradation through the ubiquitin proteasome, while ORF7a utilizes K63-linked polyubiquitin chains to prevent STAT2 phosphorylation and IFN-I signaling. The N protein of both SARS and MERS-CoV block the interaction between TRIM25 and RIG-I, preventing the K63-linked polyubiquitination of RIG-I needed for IFN-I production. TRIM25 is also a _target of inhibition by the NS1 protein of IAV and the short noncoding sfRNAs of dengue-2 (DENV2). The PLpro component of SARS-CoV is capable of antagonizing innate immune pathways by acting as a deubiquitinase and by preventing the ISGylation of cellular proteins, including IRF3. Both SARS-CoV and Zika virus (ZIKV) alter components of the host ubiquitin system to activate the NLRP3 inflammasome, potentially leading to greater dissemination of viral progeny. The NS1 protein of ZIKV can recruit the deubiquitinase USP8 to cleave the K11-linked polyubiquitin chains from Caspase-1, while the SARS-CoV ORF3a protein promotes TRAF3 and ASC association, resulting in the K63-linked ubiquitination of ASC. In addition, ubiquitination also possesses antiviral functions. TRIM6 can regulate the expression of VAMP8 to promote JAK1 phosphorylation downstream of IFN-I signaling and promote the synthesis of unanchored K48-linked polyubiquitin chains for IKKε oligomerization.
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