SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation

School of Biomedical Science, University of St. Andrews, Fife, United Kingdom.
Molecular Cell (Impact Factor: 14.02). 09/1998; 2(2):233-9.
Source: PubMed


Activation of NF-kappaB is achieved by ubiquitination and proteasome-mediated degradation of IkappaBalpha. We have detected modified IkappaBalpha, conjugated to the small ubiquitin-like protein SUMO-1, which is resistant to signal-induced degradation. In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation. As a result, overexpression of SUMO-1 inhibits signal-induced activation of NF-kappaB-dependent transcription. Unlike ubiquitin modification, which requires phosphorylation of S32 and S36, SUMO-1 modification of IkappaBalpha is inhibited by phosphorylation. Thus, while ubiquitination targets proteins for rapid degradation, SUMO-1 modification acts antagonistically to generate proteins resistant to degradation.

Download full-text


Available from: Manuel S. Rodriguez, Aug 22, 2014
  • Source
    • "The role of SENPs encompasses removal of SUMO from target proteins, thus reversing the effects induced by SUMOylation. Although SUMOylation shares similarities with ubiquitination, it has been shown that SUMO proteins compete with ubiquitin for substrate binding; thus, SUMOylation appears to protect target proteins from proteasomal degradation [28] [29] [30]. In addition to enhancing protein stability, SUMO proteins are involved in subcellular localization and distribution of modified proteins as well as inter-and intramolecular interactions of target substrates, which affect processes essential for normal and abnormal cellular homeostasis [31] [32] [33] [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK(+)) T-cell lymphoma is an aggressive form of cancer that commonly affects children and adolescents. The expression of NPM-ALK chimeric oncogene results from the chromosomal translocation t(2;5)(p23;q35) that causes the fusion of the ALK and NPM genes. This translocation generates the NPM-ALK protein tyrosine kinase that forms the constitutively activated NPM-ALK/NPM-ALK homodimers. In addition, NPM-ALK is structurally associated with wild-type NPM to form NPM/NPM-ALK heterodimers, which can translocate to the nucleus. The mechanisms that sustain the stability of NPM-ALK are not fully understood. SUMOylation is a posttranslational modification that is characterized by the reversible conjugation of small ubiquitin-like modifiers (SUMOs) with target proteins. SUMO competes with ubiquitin for substrate binding and therefore, SUMOylation is believed to protect target proteins from proteasomal degradation. Moreover, SUMOylation contributes to the subcellular distribution of target proteins. Herein, we found that the SUMOylation pathway is deregulated in NPM-ALK(+) T-cell lymphoma cell lines and primary lymphoma tumors from patients. We also identified Lys(24) and Lys(32) within the NPM domain as the sites where NPM-ALK conjugates with SUMO-1 and SUMO-3. Importantly, antagonizing SUMOylation by the SENP1 protease decreased the accumulation of NPM-ALK and suppressed lymphoma cell viability, proliferation, and anchorage-independent colony formation. One possible mechanism for the SENP1-mediated decrease in NPM-ALK levels was the increase in NPM-ALK association with ubiquitin, which facilitates its degradation. Our findings propose a model in which aberrancies in SUMOylation contribute to the pathogenesis of NPM-ALK(+) T-cell lymphoma. Unraveling such pathogenic mechanisms may lead to devising novel strategies to eliminate this aggressive neoplasm.
    Neoplasia (New York, N.Y.) 10/2015; 17(9):742-754. DOI:10.1016/j.neo.2015.09.005 · 4.25 Impact Factor
  • Source
    • "hydrocarbon receptor; APP, amyloid precursor protein; CHDs, congenital heart diseases; CSN, COP9 signalosome; GR, glucocorticoid receptor; HSFs, heat shock factors ; IPC, ischemic preconditioning; mRNP, messenger ribonucleoparticle ; NAE, NEDD8-activating enzyme; OGD, oxygen/glucose deprivation; SENPs, sentrin-specific proteases; SUMO, Small ubiquitin-related modifier types that can interplay (crosstalk) within the same or between various proteins. For example, a signal-dependent phosphorylation of protein IkB can inhibit its sumoylation and stimulate ubiquitination [1]. Various PTMs can compete for the same amino acid residue or multiple amino acid residues can be targeted by the same PTM (e.g., serine, threonine, and tyrosine residues by phosphorylation). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The alteration in proteome composition induced by environmental changes and various pathologies is accompanied by the modifications of proteins by specific co- and post-translational modifications (PTMs). The type and site stoichiometry of PTMs can affect protein functions, alter cell signaling and can have acute and chronic effects. The particular interest is drawn to those amino acid residues that can undergo several different PTMs. We hypothesize that these selected amino acid residues are biologically rare and act within the cell as molecular switches. There are, at least, twelve various lysine modifications currently known, several of them have been shown to be competitive and they influence the ability of a particular lysine to be modified by a different PTM. In this review, we discuss the PTMs that occur on lysine, specifically neddylation and sumoylation and the proteomic approaches that can be applied for the identification and quantification of these PTMs. Of interest are the emerging roles for these modifications in heart disease and what can be inferred from work in other cell types and organs. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    PROTEOMICS 03/2015; 15(5-6). DOI:10.1002/pmic.201400312 · 3.81 Impact Factor
  • Source
    • "Like other PTMs, SUMOylation is reversible and the conjugation/deconjugation mechanisms are reminiscent of the ubiquitin pathway (Muller et al., 2001). In contrast to ubiquitination though, SUMOylation does not directly target proteins for degradation but rather regulates other functions such as nuclear localization, protein–protein interactions, transcriptional activity and, interestingly, ubiquitination itself (Desterro et al., 1998; Buschmann et al., 2000). SUMOylation was first implicated in the clock following the discovery of a SUMOylation consensus motif in BMAL1 (Cardone et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Circadian rhythms, endogenous cycles of about 24 h in physiology, are generated by a master clock located in the suprachiasmatic nucleus of the hypothalamus and other clocks located in the brain and peripheral tissues. Circadian disruption is known to increase the incidence of various illnesses, such as mental disorders, metabolic syndrome, and cancer. At the molecular level, periodicity is established by a set of clock genes via autoregulatory translation-transcription feedback loops. This clock mechanism is regulated by post-translational modifications such as phosphorylation and ubiquitination, which set the pace of the clock. Ubiquitination in particular has been found to regulate the stability of core clock components but also other clock protein functions. Mutation of genes encoding ubiquitin ligases can cause either elongation or shortening of the endogenous circadian period. Recent research has also started to uncover roles for deubiquitination in the molecular clockwork. Here, we review the role of the ubiquitin pathway in regulating the circadian clock and we propose that ubiquitination is a key element in a clock protein modification code that orchestrates clock mechanisms and circadian behavior over the daily cycle.
    Frontiers in Molecular Neuroscience 08/2014; 7:69. DOI:10.3389/fnmol.2014.00069 · 4.08 Impact Factor
Show more