Viral immune modulators perturb the human molecular network by common and unique strategies.
Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies.
CeMMResearch Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Andreas
A
Pichlmair
Kumaran
K
Kandasamy
Gualtiero
G
Alvisi
Orla
O
Mulhern
Roberto
R
Sacco
Matthias
M
Habjan
Marco
M
Binder
Adrijana
A
Stefanovic
Carol-Ann
CA
Eberle
Adriana
A
Goncalves
Tilmann
T
Bürckstümmer
André C
AC
Müller
Astrid
A
Fauster
Cathleen
C
Holze
Kristina
K
Lindsten
Stephen
S
Goodbourn
Georg
G
Kochs
Friedemann
F
Weber
Ralf
R
Bartenschlager
Andrew G
AG
Bowie
Keiryn L
KL
Bennett
Jacques
J
Colinge
Giulio
G
Superti-Furga
D010450:Endopeptidases / Q000378:metabolism; D057809:HEK293 Cells; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D013058:Mass Spectrometry; D016366:Open Reading Frames / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D013379:Substrate Specificity; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014780:Viruses / Q000276:immunology* / Q000378:metabolism
D010450:Endopeptidases; D034722:Heterogeneous-Nuclear Ribonucleoprotein U; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D014764:Viral Proteins; C559917:USP19 protein, human