Rotavirus NSP1 inhibits NFkappaB activation by inducing proteasome-dependent degradation of beta-TrCP: a novel mechanism of IFN antagonism.
Mechanisms by which viruses counter innate host defense responses generally involve inhibition of one or more components of the interferon (IFN) system. Multiple steps in the induction and amplification of IFN signaling are targeted for inhibition by viral proteins, and many of the IFN antagonists have direct or indirect effects on activation of latent cytoplasmic transcription factors. Rotavirus nonstructural protein NSP1 blocks transcription of type I IFNalpha/beta by inducing proteasome-dependent degradation of IFN-regulatory factors 3 (IRF3), IRF5, and IRF7. In this study, we show that rotavirus NSP1 also inhibits activation of NFkappaB and does so by a novel mechanism. Proteasome-mediated degradation of inhibitor of kappaB (IkappaBalpha) is required for NFkappaB activation. Phosphorylated IkappaBalpha is a substrate for polyubiquitination by a multisubunit E3 ubiquitin ligase complex, Skp1/Cul1/F-box, in which the F-box substrate recognition protein is beta-transducin repeat containing protein (beta-TrCP). The data presented show that phosphorylated IkappaBalpha is stable in rotavirus-infected cells because infection induces proteasome-dependent degradation of beta-TrCP. NSP1 expressed in isolation in transiently transfected cells is sufficient to induce this effect. Targeted degradation of an F-box protein of an E3 ligase complex with a prominent role in modulation of innate immune signaling and cell proliferation pathways is a unique mechanism of IFN antagonism and defines a second strategy of immune evasion used by rotaviruses.
Graff
Joel W
JW
Veterinary Molecular Biology, Montana State University, Bozeman, Montana, United States of America.
Ettayebi
Khalil
K
Hardy
Michele E
ME
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral; D020672:I-kappa B Proteins / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012401:Rotavirus / Q000235:genetics / Q000378:metabolism*; D012400:Rotavirus Infections / Q000378:metabolism* / Q000821:virology; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
D020672:I-kappa B Proteins; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D051996:Transcription Factor RelA; D017361:Viral Nonstructural Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C104282:nsp1 protein, Rotavirus; D000072000:NF-KappaB Inhibitor alpha; D016899:Interferon-beta; D046988:Proteasome Endopeptidase Complex