Polyubiquitin chains: Polymeric protein signals

Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, MD 21205, USA.
Current Opinion in Chemical Biology (Impact Factor: 6.81). 01/2005; 8(6):610-6. DOI: 10.1016/j.cbpa.2004.09.009
Source: PubMed


The 76-residue protein ubiquitin exists within eukaryotic cells both as a monomer and in the form of isopeptide-linked polymers called polyubiquitin chains. In two well-described cases, structurally distinct polyubiquitin chains represent functionally distinct intracellular signals. Recently, additional polymeric structures have been detected in vivo and in vitro, and several large families of proteins with polyubiquitin chain-binding activity have been discovered. Although the molecular mechanisms governing specificity in chain synthesis and recognition are still incompletely understood, the scope of signaling by polyubiquitin chains is likely to be broader than originally envisioned.

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    • "Therefore, to ensure a balanced immune response that is effective against microbes but one that is not self-injurious, PRR signaling pathways are subject to stringent regulation. Ubiquitin is a 76-amino-acid polypeptide present in all eukaryotic cells (Pickart and Fushman, 2004). Ubiquitination, the covalent attachment of ubiquitins to proteins by ubiquitin ligases, has emerged as a versatile system controlling the regulation of diverse aspects of biology including immunity (Bhoj and Chen, 2009; Harhaj and Dixit, 2012; Jiang and Chen, 2012). "
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    ABSTRACT: Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response.
    Immunity 10/2015; DOI:10.1016/j.immuni.2015.09.010 · 21.56 Impact Factor
    • "Ubiquitination, as an enzymatic cascade, is well-reviewed [2] [3]. "
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    ABSTRACT: F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.
    Seminars in Cancer Biology 09/2015; DOI:10.1016/j.semcancer.2015.09.013 · 9.33 Impact Factor
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    • "What these fates are and how they are defined are also important questions. By analogy to ubiquitination, SUMO-1 and SUMO-2/3 may specify distinct fates by mediating interactions with different downstream binding partners (Pickart and Fushman, 2004). Supporting this, SUMO-binding proteins with paralog-specific binding affinities have been identified (Hecker et al., 2006). "

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