The role of ubiquitylation in immune defence and pathogen evasion

ArticleinNature Reviews Immunology 12(1):35-48 · December 2011with20 Reads
DOI: 10.1038/nri3111 · Source: PubMed
Abstract
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.
    • "After RLR stimulation, TBK1 activation is initiated at the mitochondria through the essential adaptor MAVS [2, 6]. However, active TBK1 was detected at the Golgi apparatus following Sendai virus infection suggesting the targeting of TBK1 to this organelle. "
    [Show abstract] [Hide abstract] ABSTRACT: Background After viral infection and the stimulation of some pattern-recognition receptors, TANK-binding kinase I (TBK1) is activated by K63-linked polyubiquitination followed by trans-autophosphorylation. While the activated TBK1 induces type I interferon production by phosphorylating the transcription factor IRF3, the precise molecular mechanisms underlying TBK1 activation remain unclear. ResultsWe report here the localization of the ubiquitinated and phosphorylated active form of TBK1 to the Golgi apparatus after the stimulation of RIG-I-like receptors (RLRs) or Toll-like receptor-3 (TLR3), due to TBK1 K63-linked ubiquitination on lysine residues 30 and 401. The ubiquitin-binding protein optineurin (OPTN) recruits ubiquitinated TBK1 to the Golgi apparatus, leading to the formation of complexes in which TBK1 is activated by trans-autophosphorylation. Indeed, OPTN deficiency in various cell lines and primary cells impairs TBK1 targeting to the Golgi apparatus and its activation following RLR or TLR3 stimulation. Interestingly, the Bluetongue virus NS3 protein binds OPTN at the Golgi apparatus, neutralizing its activity and thereby decreasing TBK1 activation and downstream signaling. Conclusions Our results highlight an unexpected role of the Golgi apparatus in innate immunity as a key subcellular gateway for TBK1 activation after RNA virus infection.
    Full-text · Article · Dec 2016
    • "Stimulation of these receptors triggers assembly of multi-protein signaling complexes where Ub ligases and deubiquitinases (DUBs) coordinate the deposition of Ub chains linked via lysine 63 (Lys63-Ub) and methionine 1 (Met1-Ub) on protein substrates to orchestrate activation of the TAB-TAK1 and NEMO-IKKa/b kinase complexes, respectively. Activation of IKK is required for productive signaling and NF-kB-mediated transcriptional responses , and its activation depends on the binding of Met1-Ub by the IKK subunit NEMO (also known as IKKg) (Fiil and GyrdHansen, 2014; Jiang and Chen, 2011). Met1-Ub is conjugated by the linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1, and SHARPIN, which has emerged as an important Ub ligase activity in innate immune signaling and immune regulation (Boisson et al., 2012Boisson et al., , 2015 Damgaard et al., 2012; Gerlach et al., 2011; Ikeda et al., 2011; Kirisako et al., 2006; Tokunaga et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: The linear ubiquitin chain assembly complex (LUBAC) regulates immune signaling, and its function is regulated by the deubiquitinases OTULIN and CYLD, which associate with the catalytic subunit HOIP. However, the mechanism through which CYLD interacts with HOIP is unclear. We here show that CYLD interacts with HOIP via spermatogenesis-associated protein 2 (SPATA2). SPATA2 interacts with CYLD through its non-canonical PUB domain, which binds the catalytic CYLD USP domain in a CYLD B-box-dependent manner. Significantly, SPATA2 binding activates CYLD-mediated hydrolysis of ubiquitin chains. SPATA2 also harbors a conserved PUB-interacting motif that selectively docks into the HOIP PUB domain. In cells, SPATA2 is recruited to the TNF receptor 1 signaling complex and is required for CYLD recruitment. Loss of SPATA2 increases ubiquitination of LUBAC substrates and results in enhanced NOD2 signaling. Our data reveal SPATA2 as a high-affinity binding partner of CYLD and HOIP, and a regulatory component of LUBAC-mediated NF-κB signaling.
    Full-text · Article · Aug 2016
    • "An alternative use of the acquired mosquito-originated polyubiquitin gene could be that Z. culisetae uses it as a defense against bacteria, viruses, or other microbes that coexist in the insect guts, whether for its own competitive advantage or as an ally of the host. Recent research has shown that polyubiquitin has important roles in regulating the hosts' immune and inflammatory responses (Jiang and Chen 2012; Severo et al. 2013) and is able to target nonself-entities (i.e., microbial pathogens) and assist selective autophagy (Collins and Brown 2010; Jiang Wang et al. . doi:10.1093/molbev/msw126 "
    [Show abstract] [Hide abstract] ABSTRACT: Harpellales, an early-diverging fungal lineage, is associated with the digestive tracts of aquatic arthropod hosts. Concurrent with the production and annotation of the first four Harpellales genomes, we discovered that Zancudomyces culisetae, one of the most widely distributed Harpellales species, encodes an insect-like polyubiquitin chain. Ubiquitin and ubiquitin-like proteins are universally involved in protein degradation and regulation of immune response in eukaryotic organisms. Phylogenetic analyses inferred that this polyubiquitin variant has a mosquito origin. In addition, its amino acid composition, animal-like secondary structure, as well as the fungal nature of flanking genes all further support this as a horizontal gene transfer event. The single-copy polyubiquitin gene from Z. culisetae has lower GC ratio compared to homologs of insect taxa, which implies homogenization of the gene since its putatively ancient transfer. The acquired polyubiquitin gene may have served to improve important functions within Z. culisetae, by perhaps exploiting the insect hosts’ ubiquitin-proteasome systems in the gut environment. Preliminary comparisons among the four Harpellales genomes highlight the reduced genome size of Z. culisetae, which corroborates its distinguishable symbiotic lifestyle. This is the first record of a horizontally transferred ubiquitin gene from disease-bearing insects to the gut-dwelling fungal endobiont and should invite further exploration in an evolutionary context.
    Full-text · Article · Jun 2016
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