Interplay between the virus and the ubiquitin-proteasome system: molecular mechanism of viral pathogenesis

Abstract

The ubiquitin-proteasome system (UPS) plays a central role in a wide range of fundamental cellular functions by ensuring protein quality control and through maintaining a critical level of important regulatory proteins. Viruses subvert or manipulate this cellular machinery to favor viral propagation and to evade host immune response. The UPS serves as a double-edged sword in viral pathogenesis: on the one hand, the UPS is utilized by many viruses to maintain proper function and level of viral proteins; while on the other hand, the UPS constitutes a host defense mechanism to eliminate viral components. To combat this host anti-viral machinery, viruses have evolved to employ the UPS to degrade or inactivate cellular proteins that limit viral growth. This review will highlight our current knowledge pertaining to the different roles for the UPS in viral pathogenesis.

Figure 1

Viral interaction with the host ubiquitin–proteasome system (UPS): pro-viral and anti-viral function of the UPS in viral pathogenesis. The UPS, including modification of key signaling molecules involved in innate immunity by ubiquitin or ubiquitin-like modifiers (e.g. SUMO and ISG15), represents an important host anti-viral defense mechanism. Many viruses have evolved to subvert or manipulate this cellular machinery to favor their growth and to escape host immune response. In some cases, viruses encode proteins with E3 activity or even becoming part of cellular E3 complex to degrade cellular proteins (e.g. p53, MHC-I, SAMHD1, ARGONAUTE1) that limit viral growth (blue arrow). In others they generate proteins with de-ubiquitinating or de-ubiquitinating-like activity to interfere with the host ubiquitin or ubiquitin-like (e.g. SUMO and ISG15) conjugation system to combat the host anti-viral signaling pathways (red lines). Viral protein modification by ubiquitin or SUMO is often associated with increased viral release and replication, whereas modification by ISG15 results in reduced viral protein function. Viral protein degradation is either a reflection of viral clearance by host immune response or a viral strategy to maintain an optimal level of viral protein to ensure efficient viral production. Abbreviations: E1, ubiquitin/SUMO/ISG15-activating enzyme; E2, ubiquitin/SUMO/ISG15-conjugating enzyme; E3, ubiquitin/SUMO/ISG15 ligase; ISG15, interferon-stimulated gene 15; MHC-I, major histocompatibility; SAMHD1, sterile alpha motif domain-containing protein 1 and histidine-aspartate domain-containing protein 1; INFα/β, interferon-α/β.