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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    • "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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    • "These different linkages increase the complexity of the ubiquitin system, giving rise to ubiquitin chains with distinct topology, providing structural flexibility that results in a multitude of functional outcomes. The functional roles of K48-and K63-linked ubiquitin chains have been widely investigated; K48 polyubiquitination is extensively utilized to target proteins for 26S proteasomal degradation , whereas K63-linked ubiquitination mediates protein-protein interaction in different processes (Chen and Sun, 2009; Jackson and Durocher, 2013; Woelk et al., 2007). Besides the relevance of K11 and M1 linkages in cell cycle regulation and NF-kB activation (Iwai and Tokunaga, 2009; Wickliffe et al., 2009), respectively , little is known about the writers (ubiquitin ligases), the readers (ubiquitin receptors), and the functional consequences of the other noncanonical ubiquitin chains. "
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    ABSTRACT: Graphical Abstract Highlights d RNF168 mediates K27 ubiquitination of histone H2As d K27 ubiquitination is the major ubiquitin mark on chromatin upon DNA damage d K27 is strictly required for proper activation of the DNA damage response d 53BP1, Rap80, RNF168, and RNF169 directly recognize the K27 linkage Authors In Brief Gatti et al. demonstrate that cells respond to genotoxic stress by inducing K27 ubiquitination, a modification essential for activation of the DNA damage response and DNA repair. K27 ubiquitination is generated by RNF168 and targets the N-terminal tail of histone H2As.
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