Poxvirus Interactions with the Host Ubiquitin System

Abstract

The ubiquitin system has emerged as a master regulator of many, if not all, cellular functions. With its large repertoire of conjugating and ligating enzymes, the ubiquitin system holds a unique mechanism to provide selectivity and specificity in manipulating protein function. As intracellular parasites viruses have evolved to modulate the cellular environment to facilitate replication and subvert antiviral responses. Poxviruses are a large family of dsDNA viruses with large coding capacity that is used to synthetise proteins and enzymes needed for replication and morphogenesis as well as suppression of host responses. This review summarises our current knowledge on how poxvirus functions rely on the cellular ubiquitin system, and how poxviruses exploit this system to their own advantage, either facilitating uncoating and genome release and replication or rewiring ubiquitin ligases to downregulate critical antiviral factors. Whilst much remains to be known about the intricate interactions established between poxviruses and the host ubiquitin system, our knowledge has revealed crucial viral processes and important restriction factors that open novel avenues for antiviral treatment and provide fundamental insights on the biology of poxviruses and other virus families.

Monkeypox: potential vaccine development strategies

“…Orthopoxvirus-specific immunoglobulin G and M, CD4 + and CD8 + T cells, and B cell responses were measured at ∼7–14 weeks and 1 year after exposure [ 6 ]. Recent data have also highlighted the importance of the host ubiquitin system [ 7 ]. The importance of memory γδ T cells , which play an important role in protective immunity but also have the potential to worsen the progression of autoimmunity, has been highlighted in the acquired immune memory to MPXV (shown in macaques).…”

Mpox (formerly monkeypox): pathogenesis, prevention and treatment

“…The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. 84 – 86 Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. 87 – 91 …”

Virologs, viral mimicry, and virocell metabolism: the expanding scale of cellular functions encoded in the complex genomes of giant viruses

“…Ubiquitin signaling is a critical regulator of a wide range of cellular processes, and it is not surprising that viruses have evolved strategies to manipulate this system during infection (Lant and de Motes 2021 ). The ubiquitination process involves a cascade of three enzymes: E1 Ub-activation enzymes, E2 Ub-conjugating enzymes, and E3 Ub-ligating enzymes (Komander and Rape 2012 ).…”

“…Proteasome activity appears to be particularly important early in infection where it is necessary for viral genome release (Mercer et al 2012 ). Poxviruses also encode several E3 Ub-ligases that have been shown to be important for virulence, though their precise roles remain unclear (reviewed in Lant and de Motes 2021 ).…”