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      Intracellular antibody-bound pathogens stimulate immune signaling via Fc-receptor TRIM21

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          Abstract

          Antibodies can be carried into the cell during pathogen infection where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we show that TRIM21 recognition of intracellular antibodies activates immune signaling. TRIM21 catalyses K63-ubiquitin chain formation, stimulating transcription factor pathways NF-κB, AP-1 and IRF3, IRF5, IRF7. Activation results in proinflammatory cytokine production, modulation of natural killer (NK) stress ligands and the induction of an antiviral state. Intracellular antibody signaling is abrogated by genetic deletion of TRIM21 and is recovered by ectopic TRIM21 expression. Antibody sensing by TRIM21 can be stimulated upon infection by DNA or RNA non-enveloped viruses or intracellular bacteria. The antibody-TRIM21 detection system provides potent, comprehensive innate immune activation, independent of known pattern recognition receptors.

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          Direct Activation of Protein Kinases by Unanchored Polyubiquitin Chains

          Zong-Ping Xia, Lijun Sun, Xiang Chen … (2009)
          TRAF6 is a ubiquitin ligase essential for the activation of NF-κB and MAP kinases in multiple signaling pathways including those emanating from the interleukin-1 and Toll-like receptors (IL-1R/TLR)1-3. TRAF6 functions together with a ubiquitin-conjugating enzyme complex consisting of Ubc13 and Uev1A to catalyze Lys-63 (K63)-linked polyubiquitination, which activates the TAK1 kinase complex4,5. TAK1 in turn phosphorylates and activates IκB kinase (IKK), leading to activation of NF-κB. Although several proteins are known to be polyubiquitinated in the IL-1R/TLR pathways, it is not clear whether ubiquitination of any of these proteins is important for TAK1 or IKK activation. Herein, we reconstituted TAK1 activation in vitro using purified proteins and found that free K63 polyubiquitin chains, which are not conjugated to any target protein, directly activated TAK1 through binding to the ubiquitin receptor TAB2. This binding leads to autophosphorylation and activation of TAK1. We also found that unanchored polyubiquitin chains synthesized by TRAF6 and Ubc5 activated the IKK complex. Disassembly of the polyubiquitin chains by deubiquitination enzymes prevented TAK1 and IKK activation. These results indicate that unanchored polyubiquitin chains directly activate TAK1 and IKK, suggesting a novel mechanism of protein kinase regulation.
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            Salmonella maintains the integrity of its intracellular vacuole through the action of SifA.

            C Beuzón, S Méresse, K E Unsworth … (2000)
            A method based on the Competitive Index was used to identify Salmonella typhimurium virulence gene interactions during systemic infections of mice. Analysis of mixed infections involving single and double mutant strains showed that OmpR, the type III secretion system of Salmonella pathogenicity island 2 (SPI-2) and SifA [required for the formation in epithelial cells of lysosomal glycoprotein (lgp)-containing structures, termed Sifs] are all involved in the same virulence function. sifA gene expression was induced after Salmonella entry into host cells and was dependent on the SPI-2 regulator ssrA. A sifA(-) mutant strain had a replication defect in macrophages, similar to that of SPI-2 and ompR(-) mutant strains. Whereas wild-type and SPI-2 mutant strains reside in vacuoles that progressively acquire lgps and the vacuolar ATPase, the majority of sifA(-) bacteria lost their vacuolar membrane and were released into the host cell cytosol. We propose that the wild-type strain, through the action of SPI-2 effectors (including SpiC), diverts the Salmonella-containing vacuole from the endocytic pathway, and subsequent recruitment and maintenance of vacuolar ATPase/lgp-containing membranes that enclose replicating bacteria is mediated by translocation of SifA.
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              Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].

              Dietrich Conze, Jonathan Ashwell, Tao Li … (2006)
              The transcription factor NF-kappaB is sequestered in the cytoplasm in a complex with IkappaB. Almost all NF-kappaB activation pathways converge on IkappaB kinase (IKK), which phosphorylates IkappaB resulting in Lys 48-linked polyubiquitination of IkappaB and its degradation. This allows migration of NF-kappaB to the nucleus where it regulates gene expression. IKK has two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma or NEMO. NEMO is essential for NF-kappaB activation, and NEMO dysfunction in humans is the cause of incontinentia pigmenti and hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). The recruitment of IKK to occupied cytokine receptors, and its subsequent activation, are dependent on the attachment of Lys 63-linked polyubiquitin chains to signalling intermediates such as receptor-interacting protein (RIP). Here, we show that NEMO binds to Lys 63- but not Lys 48-linked polyubiquitin, and that single point mutations in NEMO that prevent binding to Lys 63-linked polyubiquitin also abrogates the binding of NEMO to RIP in tumour necrosis factor (TNF)-alpha-stimulated cells, the recruitment of IKK to TNF receptor (TNF-R) 1, and the activation of IKK and NF-kappaB. RIP is also destabilized in the absence of NEMO binding and undergoes proteasomal degradation in TNF-alpha-treated cells. These results provide a mechanism for NEMO's critical role in IKK activation, and a key to understanding the link between cytokine-receptor proximal signalling and IKK and NF-kappaB activation.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Journal ID (iso-abbrev): Nat. Immunol.
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 4 February 2013
                Publication date (Electronic): 03 March 2013
                Publication date (Print): April 2013
                Publication date PMC-release: 01 October 2013
                Volume: 14
                Issue: 4
                Pages: 327-336
                Affiliations
                [1 ]Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, CB2 0QH, United Kingdom.
                Author notes
                [* ]Correspondence to be addressed to: wmcewan@ 123456mrc-lmb.cam.ac.uk and lcj@ 123456mrc-lmb.cam.ac.uk
                Article
                Manuscript ID: EMS51130
                DOI: 10.1038/ni.2548
                PMC ID: 3672961
                PubMed ID: 23455675
                SO-VID: 34904ba3-9008-419d-8124-c42d879559e5
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: Medical Research Council :
                Award ID: U.1051.03.017(81010) || MRC_
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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