Review
How viruses hijack cell regulation

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Viruses, as obligate intracellular parasites, are the pathogens that have the most intimate relationship with their host, and as such, their genomes have been shaped directly by interactions with the host proteome. Every step of the viral life cycle, from entry to budding, is orchestrated through interactions with cellular proteins. Accordingly, viruses will hijack and manipulate these proteins utilising any achievable mechanism. Yet, the extensive interactions of viral proteomes has yielded a conundrum: how do viruses commandeer so many diverse pathways and processes, given the obvious spatial constraints imposed by their compact genomes? One important approach is slowly being revealed, the extensive mimicry of host protein short linear motifs (SLiMs).

Section snippets

Introduction to motif biology

When viruses infect cells they provide some of their own molecular equipment such as DNA/RNA polymerases, helicases and proteases. These enzymes enable replication and expression of the proteome, and viral maturation. However, this still requires that, as soon as the cell is invaded, the virus readily interferes with host cell regulation to render the infected cells amenable to viral replication. Molecular virology studies have been fruitful, providing many details of the steps necessary to

Prevalence of motif mimicry

Only a handful of the eukaryotic motifs known to be mimicked by viruses, such as the ubiquitous ‘late domains’ of small enveloped RNA viruses 4, 11, 12, 13, 14, and the LxCxE motif-mediated deregulation of the S-phase checkpoint retinoblastoma protein (RB) 3, 15, 16, have been studied in detail, and little has been written about the extent of motif mimicry as a concerted tactic utilised by viruses to reprogram the host cell. However, sparse literature reveals compelling evidence that convergent

Diversity of hijacked functionality

The range of functions and the diverse set of host pathways targeted already encompass the full complement of motif functionality (Figure 1b). Crucially, the available instances reveal a telling insight into the varied mechanisms by which viruses utilise these motifs. In the following section we will present an overview of these mechanisms and functions.

Why do viruses use motifs so extensively?

Large swaths of the regulatory functionality of a cell are controlled by SLiMs, and their short and degenerate nature enables convergent evolution of novel motif instances to be very rapid relative to typical evolutionary timescales [7]. SLiMs are therefore adaptations that allow evolution to quickly rewire cellular regulatory pathways [10], making them a convergently evolvable toolbox of protein modules. Unfortunately (from the human perspective), they are equally available to the much faster

Concluding remarks

Mimicry is an important tactic used in interspecies interactions with multiple examples, ranging from mammals to viruses [84]. In this review, we describe one of the simplest and most evolutionarily accessible forms of mimicry, the imitation of host SLiM modules. The focus is on viral mimicry, but note that examples can also be found for invasive bacteria (e.g. [85]). Many motifs (TSG101, RB, importin and C-terminal-binding protein 1 (CtBP) binding motifs 1, 2, 3, 4) were originally discovered

Acknowledgements

We would like to thank our colleagues at EMBL, ESBS and elsewhere for many useful discussions. We also thank Holger Dinkel, John Briggs, Ricardo Rodriguez De La Vega, Katja Luck and Gráinne Kerr for their helpful comments on the manuscripts. N.E.D. was supported by an EMBL Interdisciplinary Postdoc (EIPOD) fellowship from EMBL.

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