Viruses and interactomes in translation

Abstract

A decade of high-throughput screenings for intraviral and virus-host protein-protein interactions led to the accumulation of data and to the development of theories on laws governing interactome organization for many viruses. We present here a computational analysis of intraviral protein networks (EBV, FLUAV, HCV, HSV-1, KSHV, SARS-CoV, VACV, and VZV) and virus-host protein networks (DENV, EBV, FLUAV, HCV, and VACV) from up-to-date interaction data, using various mathematical approaches. If intraviral networks seem to behave similarly, they are clearly different from the human interactome. Viral proteins target highly central human proteins, which are precisely the Achilles' heel of the human interactome. The intrinsic structural disorder is a distinctive feature of viral hubs in virus-host interactomes. Overlaps between virus-host data sets identify a core of human proteins involved in the cellular response to viral infection and in the viral capacity to hijack the cell machinery for viral replication. Host proteins that are strongly targeted by a virus seem to be particularly attractive for other viruses. Such protein-protein interaction networks and their analysis represent a powerful resource from a therapeutic perspective.

Fig. 1.

Intraviral protein-protein interaction networks. VACV (dark blue), SARS-CoV (red), HSV-1 (green), HCV (brown), FLUAV (gray), VZV (light blue), EBV (magenta), and KSHV (orange). Node: viral protein. Edge: virus-virus protein-protein interaction. Nodes are ordered according to a degree sorted circle layout. Nodes are labeled according to the NCBI protein definition (for some imprecisely defined VACV proteins, the NCBI gene name or locus tag was used).

Fig. 2.

Random failure and deliberate attack tolerance of intraviral and human interactomes. A, Changes in the characteristic path length (CPL) (as a multiple of the original value) during the progressive random removal of nodes in intraviral and human interactomes, simulating random failures. B, Changes in the network size, i.e. number of nodes, (as a fraction of the original value) during the progressive random removal of nodes in intraviral and human interactomes, simulating random failures. C, Changes in the characteristic path length (CPL) (as a multiple of the original value) during the progressive removal of nodes in degree-decreasing order in intraviral and human interactomes, simulating deliberate attacks. D, Changes in the network size, i.e. number of nodes, (as a fraction of the original value) during the progressive removal of nodes in degree-decreasing order in intraviral and human interactomes, simulating deliberate attacks.

Fig. 3.

Virus-host protein-protein interaction networks. DENV-human interactome (H-DENV), EBV-human interactome (H-EBV), FLUAV-human interactome (H-FLUAV), HCV-human interactome (H-HCV), and VACV-human interactome (H-VACV). Black node: viral protein; red node: human protein, red edge: virus-host protein-protein interaction; blue edge: host-host protein-protein interaction. Nodes are ordered according to a force directed layout. Viral protein nodes are labeled according to the NCBI protein definition (for some imprecisely defined VACV proteins, the NCBI gene name or locus tag was used).

Fig. 4.

Disorder-degree analysis of viral proteins in virus-host interactomes. Mean percentage of residues predicted to be disordered (y axis) within segments of various lengths (x axis) in sequences of viral proteins interacting with cellular proteins. Data from the five virus-host interactomes have been analyzed. Viral ends (black line) are viral proteins having only one human interacting protein. Viral hubs (colored lines) are viral proteins highly connected to human proteins. Various degree thresholds were used to define the set of hubs: at least 15 (violet line), at least 20 (blue line), at least 25 (turquoise line), at least 30 (green line), at least 50 (yellow line), at least 60 (orange line) and at least 100 human interactors (red line).

Fig. 5.

Topological analysis of the virus-host interactomes. A, Metrics of the human proteins and of the human proteins targeted by viruses in the human interactome. The number of nodes and edges, the mean degree, the mean adjusted betweenness and the characteristic path length are given first for all the human proteins, then for the human proteins targeted by DENV, EBV, FLUAV, HCV, and VACV. B, Degree distributions of human proteins and human proteins targeted by viruses in the human interactome. P(k) is the probability of a node to connect k other nodes in the network. Solid lines represent linear regression fits. Vertical dashed lines indicate the mean degree of each distribution. C, Betweenness distributions of human proteins and human proteins targeted by viruses in the human interactome. P(b) is the probability for a node to have a betweenness value of b in the network. Solid lines represent linear regression fits. Vertical dashed lines indicate the mean betweenness value for each distribution.