Chen ZJ, Sun LJ.. Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33: 275-286

Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Molecular cell (Impact Factor: 14.02). 03/2009; 33(3):275-86. DOI: 10.1016/j.molcel.2009.01.014
Source: PubMed


The small protein ubiquitin is a central regulator of a cell's life and death. Ubiquitin is best known for targeting protein destruction by the 26S proteasome. In the past few years, however, nonproteolytic functions of ubiquitin have been uncovered at a rapid pace. These functions include membrane trafficking, protein kinase activation, DNA repair, and chromatin dynamics. A common mechanism underlying these functions is that ubiquitin, or polyubiquitin chains, serves as a signal to recruit proteins harboring ubiquitin-binding domains, thereby bringing together ubiquitinated proteins and ubiquitin receptors to execute specific biological functions. Recent advances in understanding ubiquitination in protein kinase activation and DNA repair are discussed to illustrate the nonproteolytic functions of ubiquitin in cell signaling.

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    • "These complex and varied structures enable ubiquitination to transmit diverse functional signals that determine the fate of a substrate protein. The well-studied K63-linked chains mediate the functions of various cellular proteins involved in inflammatory signaling complexes, whereas K48-linked chains predominantly facilitate the proteasomal-mediated degradation of substrates (Hershko and Ciechanover, 1998; Chen and Sun, 2009). To date, other types of ubiquitin linkages have not been well studied and are usually referred to as atypical ubiquitinations. "
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    ABSTRACT: Ubiquitination, also denoted ubiquitylation, is a posttranslational modification that has been implicated in the regulation of both innate and adaptive immune responses. Ubiquitination plays crucial roles in innate immune signaling by ensuring the proper orchestration of several signaling mediators that constitute a functional immune response. Herein, we briefly summarize the latest discoveries concerning the molecular ubiquitination-related machinery that senses, assembles, and disassembles innate immune signaling mediators. Introduction The mammalian immune system, which involves a complex yet tightly regulated network of interactions among different types of cells, cell receptors, and signaling pathways, constantly battles invading pathogens. In addition to the aforementioned immune-system participants, its specificity and complexity also depend on posttranslational modifications of proteins involved in the initiation, maintenance, and termination of immune responses. These posttranslational modifications involve the addition of a chemical group or another protein(s) at one or more site of substrate. To date, more than 200 types of posttranslational modifications have been reported (Kho et al., 2004); with phosphorylation, ubiquitination, and sumoylation being the most extensively studied and well characterized. Ubiquitination is a key posttranslational modification regulating numerous biological processes at various cellular levels, e.g., protein trafficking, the cell cycle, and immune responses. The addition of ubiquitin to a substrate protein usually involves three main steps: activation by a ubiquitin-activating enzyme (E1), conjugation by a
    Current issues in molecular biology 07/2016; 18(1):1-10. · 5.75 Impact Factor
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    • "Different linkages have different functional specificities [7]. Lys48- and Lys63-linked polyUb chains are linked to protein degradation [8] and cellular signaling [9], whereas the role of the remaining Ub chain types, often indicated as " atypical " chains, is less understood [10]. Lys11 and Met1 linkages seem to be involved in cell cycle regulation and nuclear factor-kB activation, respectively [11] [12]. "
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    ABSTRACT: Attachment of ubiquitin (Ub) as mono- and polyUb chains of different lengths and linkages to proteins plays a dominant role in very different regulatory mechanisms. Therefore, the study of polyUb chains has assumed a central interest in Biochemistry and Structural Biology. An essential step necessary to allow in vitro biochemical and structural studies of polyUbs is the production of their chains in high quantities and purity. This not always easy task can be achieved both enzymatically and chemically. Previous reviews have covered chemical cross-linking exhaustively. In this review, we concentrate on the different approaches developed so far for the enzymatic production of different Ub chains. These strategies permit a certain flexibility in the production of chains with various linkages and lengths. We critically describe the available methods and comment on advantages and limitations. It is clear that the field is mature to study most of the possible links but some more work needs to be done to complete the work and to exploit the current methodologies for understanding in full the Ub code.
    Analytical Biochemistry 10/2015; DOI:10.1016/j.ab.2015.09.013 · 2.22 Impact Factor
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    • "The range of substrateubiquitin structures is important for the targeting of ubiquitinated substrates to different fates. For example, K11-and K48-linked polyubiquitin chains generally target proteins for proteasomal degradation [7], while K63-linked chains can regulate kinase activation, DNA damage tolerance, signal transduction, and endocytosis [8] [9]. Modulation of protein–protein interactions is an important mechanism involved in the assembly, amplification and transmission of intracellular signals. "
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    ABSTRACT: The presenilins (PS1 and PS2) are the catalytic component of the γ-secretase intramembrane protease complex, involved in the regulated intramembrane proteolysis of numerous type I transmembrane proteins, including Amyloid precursor protein (APP) and Notch. Herein, we describe the identification and characterization of a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin-binding domain (UBD) in PS1, and demonstrate that the CUE domain of PS1 mediates non-covalent binding to Lysine 63-linked polyubiquitin chains. Our results highlight a γ-secretase-independent function for non-covalent ubiquitin signalling in the regulation of PS1, and add new insights into the structure and function of the presenilin proteins. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 03/2015; 589(9). DOI:10.1016/j.febslet.2015.03.008 · 3.17 Impact Factor
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