title: Profiling of the kinome of cytomegalovirus-infected cells reveals the functional importance of host kinases Aurora A, ABL and AMPK.
abstract: Human cytomegalovirus infection can lead to life-threatening clinical manifestations particularly in the immunocompromised host. Current therapy options face severe limitations leading to a continued search for alternative drug candidates. Viral replication is dependent on a balanced interaction between viral and cellular proteins. Especially protein kinases are important regulators of virus-host interaction indicated by remarkable kinome alterations induced upon HCMV infection. Here we report a novel approach of kinome profiling with an outcome that suggests an important role of specific cellular protein kinases, such as AMPK, ABL2 and Aurora A. Inhibition of AMPK and ABL kinases showed a significant reduction, whereas inhibition of Aurora A kinase led to a slight activation of HCMV replication, as measured in a GFP reporter-based replication assay. Furthermore, analysis of the mode of antiviral action suggested a substantial benefit for the efficiency of viral replication at the immediate early (AMPK) or early-late (ABL) phases of HCMV gene expression. In contrast, inhibition of Aurora A kinase promoted an enhancement of viral early-late gene expression, suggesting a putative role of Aurora A signaling in host defense. Thus, the combined data provide new information on host cell kinases involved in viral replication and uncovered potential targets for future antiviral strategies.
authors: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany. corina.hutterer@viro.med.uni-erlangen.de
authors: Corina
authors: C
authors: Hutterer
authors: Sebastian Karl
authors: SK
authors: Wandinger
authors: Sabrina
authors: S
authors: Wagner
authors: Regina
authors: R
authors: Müller
authors: Thomas
authors: T
authors: Stamminger
authors: Isabel
authors: I
authors: Zeitträger
authors: Klaus
authors: K
authors: Godl
authors: Roland
authors: R
authors: Baumgartner
authors: Stefan
authors: S
authors: Strobl
authors: Manfred
authors: M
authors: Marschall
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000201:enzymology* / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D000090742:Serine-Threonine Kinase 3; D014779:Virus Replication / Q000187:drug effects; D000099317:Hippo Kinases
chemical_list: D055372:AMP-Activated Protein Kinases; D000998:Antiviral Agents; D064096:Aurora Kinase A; D001549:Benzamides; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016315:Proto-Oncogene Proteins c-abl; D011743:Pyrimidines; D000090742:Serine-Threonine Kinase 3; C095566:STK4 protein, human; D000099317:Hippo Kinases; C097835:STK3 protein, human; C547386:ULK3 protein, human
keywords: Antiviral targets; Host cell kinome; Human cytomegalovirus; Kinase inhibitors; Mass spectrometry-based profiling; Regulatory protein kinases