Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection

Abstract

Ubiquitin is important for nearly every aspect of cellular physiology. All viruses rely extensively on host machinery for replication; therefore, it is not surprising that viruses connect to the ubiquitin pathway at many levels. Viral involvement with ubiquitin occurs either adventitiously because of the unavoidable usurpation of cellular processes, or for some specific purpose selected for by the virus to enhance viral replication. Here, we review current knowledge of how the ubiquitin pathway alters viral replication and how viruses influence the ubiquitin pathway to enhance their own replication.

Figure 1

Schematic of Ubiquitin or Ubiquitin-Like Modifier Conjugation and Deconjugation during Viral Infection Processed ubiquitin (Ub) or ubiquitin-like modifier (Ubl) is activated with ATP by an E1 ubiquitin-activating enzyme (1) and then transferred to an E2 ubiquitin-conjugating enzyme (2). The Ub/Ubl is then ligated to a substrate via the action of an E3 ubiquitin ligase (3). The E3 determines substrate specificity and can be either cellular or viral in origin. The ubiquitinated substrate is then released (4) and can be polyubiquitinated, often leading to proteasome-mediated degradation (5), or the Ub/Ubl can be removed via the action of a cellular or viral deubiquitinating enzyme (DUB) (6). Alternatively, in the course of viral infection, a viral protein can bind to a cellular ubiquitin ligase complex, altering substrate specificity (7). The substrate is released after ubiquitin conjugation (8).

Figure 2

Viral Interference with the Host Immune Response Class I MHC molecules are dislocated from the ER in response to HCMV viral proteins US2/US11 or MHV-68 mk3 protein. KSHV K3 and K5 proteins mediate ubiquitination and downregulation of class I MHC molecules at the cell surface. HIV Vif induces the formation of an E3 ubiquitin ligase complex, which binds to and ubiquitinates APOBEC3G, leading to its degradation and preventing its incorporation into HIV virions. Expression of antiviral ubiquitin-like modifier, ISG15, is induced upon infection of certain viruses, including influenza B. The NS1B protein of influenza inhibits the UBE1L ligase and prevents conjugation of ISG15 to substrates. Some viruses also encode deubiquitinating enzymes that mediate removal of ISG15 from substrates. Abbreviations: ISRE, interferon sensitive responsive element; Ub, ubiquitin.