Abstract
The ubiquitin conjugation system regulates a wide variety of biological phenomena, in most cases, by modulating protein function via polyubiquitin conjugation. Several types of polyubiquitin chains exist in cells and the type of chain conjugated to a protein seems to determine how the protein is regulated. The polyubiquitin chains that have been reported thus far are generated by conjugation via Lys residues of ubiquitin. We have identified a novel linear polyubiquitin chain, in which the C-terminal Gly of one ubiquitin is conjugated to the α-amino group of the N-terminal Met of another ubiquitin and the ubiquitin ligase complex mediating these reactions specifically generates linear chains. We have shown that linear polyubiquitination is involved in activation of the canonical NF-κB pathway. The regulatory roles of Lys63-linked ubiquitin chains in the NF-κB path way have been extensively studied. In this chapter, we will discuss the distinct roles of linear and K63-linked ubiquitin chains in TNF-α mediated NF-κB activation and the future directions for linear ubiquitin chain research.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002; 82:373–428.
Hicke L, Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol 2003; 19:141–72.
Chau V, Tobias JW, Bachmair A et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 1989; 243:1576–83.
Kerscher O, Felberbaum R, Hochstrasser M. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol 2006; 22:159–80.
Peng J, Schwartz D, Elias JE et al. A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 2003; 21:921–6.
Jin L, Williamson A, Banerjee S et al. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell 2008; 133:653–65.
Kirisako T, Kamei K, Murata S et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J 2006; 25:4877–87.
Chen Z, Pickart CM. A 25-kilodalton ubiquitin carrier protein (E2) catalyzes multi-ubiquitin chain synthesis via lysine 48 of ubiquitin. J Biol Chem 1990; 265:21835–42.
Iwai K, Tokunaga F. Linear polyubiquitination: a new regulator of NF-κB activation. EMBO Rep 2009; 10:706–13.
Hofmann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 1999; 96:645–53.
Hayden MS, Ghosh S. Shared principles in NF-κB signaling. Cell 2008; 132:344–62.
Hacker H, Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE 2006; re13.
Tokunaga F, Sakata S, Saeki Y et al. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nat Cell Biol 2009; 11:123–32.
Lo YC, Lin SC, Rospigliosi CC et al. Structural basis for recognition of diubiquitins by NEMO. Mol Cell 2009; 33:602–15.
Rahighi S, Ikeda F, Kawasaki M et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 2009; 136:1098–109.
Dai YS, Liang MG, Gellis SE et al. Characteristics of mycobacterial infection in patients with immunodeficiency and nuclear factor-κB essential modulator mutation, with or without ectodermal dysplasia. J Am Acad Dermatol 2004; 51:718–22.
Filipe-Santos O, Bustamante J, Haverkamp MH et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med 2006; 203:1745–59.
Chen ZJ, Sun LJ. Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 2009; 33:275–86.
Ea CK, Deng L, Xia ZP et al. Activation of IKK by TNFa requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 2006; 22:245–57.
Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular signals. ‘Protein Modifications: Beyond the Usual Suspects’ review series. EMBO Rep 2008; 9:536–42.
Yamamoto M, Okamoto T, Takeda K et al. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 2006; 7:962–70.
Rape M. Ubiquitin, infinitely seductive: symposium on the many faces of ubiquitin. EMBO Rep 2009; 10:558–62.
Yamamoto M, Sato S, Saitoh T et al. Cutting Edge: Pivotal function of Ubc13 in thymocyte TCR signaling. J Immunol 2006; 177:7520–4.
Finley D, Ozkaynak E, Varshavsky A. The yeast polyubiquitin gene is essential for resistance to high temperatures, starvation and other stresses. Cell 1987; 48:1035–46.
Turner GC, Varshavsky A. Detecting and measuring cotranslational protein degradation in vivo. Science 2000; 289:2117–20.
Nakamura M, Tokunaga F, Sakata S, Iwai K. Mutual regulation of conventional protein kinase C and a ubiquitin ligase complex. Biochem Biophys Res Commun 2006; 351:340–7.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Iwai, K. (2010). Functions of Linear Ubiquitin Chains in the NF-κB Pathway. In: Groettrup, M. (eds) Conjugation and Deconjugation of Ubiquitin Family Modifiers. Subcellular Biochemistry, vol 54. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6676-6_8
Download citation
DOI: https://doi.org/10.1007/978-1-4419-6676-6_8
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-6675-9
Online ISBN: 978-1-4419-6676-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)