I B Kinase -Dependent Phosphorylation and Degradation of X-Linked Inhibitor of Apoptosis Sensitizes Cells to Virus-Induced Apoptosis

Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Canada.
Journal of Virology (Impact Factor: 4.44). 11/2011; 86(2):726-37. DOI: 10.1128/JVI.05989-11
Source: PubMed


X-linked inhibitor of apoptosis (XIAP) is a potent antagonist of caspase 3-, 7-, and 9-dependent apoptotic activities that
functions as an E3 ubiquitin ligase, and it targets caspases for degradation. In this study, we demonstrate that Sendai virus
(SeV) infection results in the IKKε- or TBK1-mediated phosphorylation of XIAP in vivo at Ser430, resulting in Lys48-linked autoubiquitination at Lys322/328 residues, followed by the subsequent proteasomal degradation of XIAP. Interestingly,
IKKε expression and XIAP turnover increases SeV-triggered mitochondrion-dependent apoptosis via the release of caspase 3,
whereas TBK1 expression does not increase apoptosis. Interestingly, phosphorylation also regulates XIAP interaction with the
transcription factor IRF3, suggesting a role in IRF3-Bax-mediated apoptosis. Our findings reveal a novel function of IKKε
as a regulator of the virus-induced triggering of apoptosis via the phosphorylation-dependent turnover of XIAP.

Download full-text


Available from: Rongtuan Lin
  • [Show abstract] [Hide abstract]
    ABSTRACT: The inhibitor of apoptosis (IAP) genes are critical regulators of multiple pathways that control cell death, proliferation, and differentiation. Several members of the IAP family regulate innate and adaptive immunity through modulation of signal transduction pathways, cytokine production, and cell survival. The regulation of immunity by the IAPs is primarily mediated through the ubiquitin ligase function of cellular IAP (cIAP)1, cIAP2, and X-linked IAP (XIAP), the targets of which impact nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, neuronal apoptosis inhibitory protein (NAIP), cIAP1, and cIAP2 modulate innate immune responses through control of the inflammasome complex. This review examines the role of mammalian IAPs in regulating immunity and describes the implications of a new class of pan-IAP antagonists for the treatment of immune disorders.
    No preview · Article · Jul 2012 · Trends in Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NEMO is a key component of antiviral signaling. Belgnaoui et al. (2012) discover that linear ubiquitination of NEMO at a late phase of virus infection switches NEMO from a positive to a negative regulator of RIG-I-mediated interferon (IFN) induction by disrupting the VISA/MAVS-TRAF3 complex and thus terminating the antiviral response.
    Preview · Article · Aug 2012 · Cell host & microbe
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell death regulation is vital for maintenance of homeostasis and proper development of multicellular organisms. Inhibitor of apoptosis (IAP) proteins are implicated in multiple ways in cell death regulation, ranging from inhibition of apoptosis and necrosis to the regulation of cell cycle and inflammation. Due to their prominent ability to control cell death and elevated expression in a variety of cancer cell types, IAP proteins are attractive targets for the development of novel anti-cancer treatments. The most widely used strategy for targeting IAP proteins is based on mimicking the natural IAP antagonist, SMAC/DIABLO. IAP antagonists are currently being tested in humans and they were designed for anti-cancer therapy but they could potentially also be considered for treatments of the immune system disorders. In this manuscript we will review the functional roles of IAP proteins, specifically of c-IAP1, c-IAP2, ML-IAP and XIAP, and evaluate IAP targeting strategies for disease treatments. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".
    Preview · Article · Oct 2012 · Experimental oncology
Show more