The role of ubiquitylation in immune defence and pathogen evasion

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 12/2011; 12(1):35-48. DOI: 10.1038/nri3111
Source: PubMed


Ubiquitylation is a widely used post-translational protein modification that regulates many biological processes, including immune responses. The role of ubiquitin in immune regulation was originally uncovered through studies of antigen presentation and the nuclear factor-κB family of transcription factors, which orchestrate host defence against microorganisms. Recent studies have revealed crucial roles of ubiquitylation in many aspects of the immune system, including innate and adaptive immunity and antimicrobial autophagy. In addition, mounting evidence indicates that microbial pathogens exploit the ubiquitin pathway to evade the host immune system. Here, we review recent advances on the role of ubiquitylation in host defence and pathogen evasion.

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    • "signaling is extensively modulated by ubiquitin at various points (Belgnaoui et al., 2012; Jiang et al., 2012; Maelfait and Beyaert, 2012; Nakhaei et al., 2009b; Zeng et al., 2010; Zeng et al., 2009; Zhong et al., 2010). Notably, the ubiquitin ligase RNF5 (RMA1) catalyzes K48-linked polyubiquitination of STING, promoting the proteasome-mediated degradation of STING (Zhong et al., 2009). "
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    ABSTRACT: Stimulator of interferon genes (STING, also known as MITA, ERIS, or MPYS) is essential for host immune responses triggered by microbial DNAs. However, the regulatory mechanisms underlying STING-mediated signaling are not fully understood. We report here that, upon cytoplasmic DNA stimulation, the endoplasmic reticulum (ER) protein AMFR was recruited to and interacted with STING in an insulin-induced gene 1 (INSIG1)-dependent manner. AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of STING. This modification served as an anchoring platform for recruiting TANK-binding kinase 1 (TBK1) and facilitating its translocation to the perinuclear microsomes. Depletion of AMFR or INSIG1 impaired STING-mediated antiviral gene induction. Consistently, myeloid-cell-specific Insig1(-/-) mice were more susceptible to herpes simplex virus 1 (HSV-1) infection than wild-type mice. This study uncovers an essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the STING signaling pathway. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6):919-933. DOI:10.1016/j.immuni.2014.11.011 · 21.56 Impact Factor
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    • "The Pellino family E3 ubiquitin ligases are implicated in TLR signaling (51). Pellino-1-deficient mice display impaired TRIF-dependent NF-κB activation and cytokine production (52). "
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    ABSTRACT: Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
    Frontiers in Immunology 09/2014; 5:461. DOI:10.3389/fimmu.2014.00461
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    • "Modifying a protein with ubiquitin can result in a variety of outcomes other than degradation. These include activation of signaling proteins, regulation of protein-protein interactions, and relocalization of proteins within a cell (Jiang and Chen, 2012). Herein, we focus on the degradation of ubiquitylated proteins. "
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    ABSTRACT: Pathogens use various mechanisms to manipulate host processes to promote infection. Decades of research on pathogens have revealed not only the molecular mechanisms that these microbes use to replicate and survive within host cells, but also seminal information on how host signaling machinery regulates cellular processes. Among these discoveries are mechanisms involving posttranslational modifications that alter the activity, localization, or interactions of the modified protein. Herein, we examine how pathogens have contributed to our basic understanding of three posttranslational modifications: phosphorylation, NMPylation, and ubiquitylation. Over the years, technologies, techniques and research tools have developed side by side with the study of pathogens, facilitating the discovery of protein modifications and furthering our understanding of how they contribute to both infection and cellular functions.
    Cell host & microbe 09/2013; 14(3):269-79. DOI:10.1016/j.chom.2013.07.008 · 12.33 Impact Factor
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