Marburg Virus VP24 Protein Relieves Suppression of the NF-κB Pathway Through Interaction With Kelch-like ECH-Associated Protein 1.
BACKGROUND
Marburg virus (MARV) is an emerging zoonotic pathogen that causes hemorrhagic fever. MARV VP24 (mVP24) protein interacts with the host cell protein Kelch-like-ECH-associated protein 1 (Keap1). Keap1 interacts with and promotes the degradation of IκB kinase β (IKKβ), a component of the IκB kinase (IKK) complex that regulates nuclear factor-κB (NF-κB) activity. We studied whether mVP24 could relieve Keap1 repression of the NF-κB pathway.


METHODS
Coimmunoprecipitation assays were used to examine the interaction between Keap1 and IKKβ in the presence of wild-type mVP24 and mutants of mVP24 defective for binding to Keap1. Western blotting was used to determine levels of IKKβ expression in the presence of Keap1 and mVP24. NF-κB promoter-luciferase assays were used to determine the effect of mVP24 on Keap1-induced repression of activity.


RESULTS
Expression of wild-type mVP24 disrupted the interaction of IKKβ and Keap1, whereas weakly interacting and noninteracting mVP24 mutants did not disrupt the interaction between Keap1 and IKKβ. The interaction of mVP24 with Keap1 enhanced IKKβ levels in the presence of Keap1. The interaction of mVP24 with Keap1 also relieved Keap1 repression of NF-κB reporter activity.


CONCLUSIONS
mVP24 can relieve Keap1 repression of the NF-κB pathway through its interaction with Keap1.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York.
Megan R
MR
Edwards
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York.
Christopher F
CF
Basler
D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008379:Marburg Virus Disease / Q000378:metabolism / Q000821:virology; D029024:Marburgvirus / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014764:Viral Proteins / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D016328:NF-kappa B; C094002:VP24 protein, Marburg virus; D014764:Viral Proteins; D051550:I-kappa B Kinase
Filovirus; Keap1; Marburg virus; NF-κB pathway; VP24