首页
400-620-6333
CXCR4: Receptor for extracellular ubiquitin
Ubiquitin is a small protein found in all eukaryotes. The covalent attachment of ubiquitin to intracellular proteins is called ubiquitination. Ubiquitination is a multistep enzymatic process requiring E1 activating enzymes, E2 binding enzymes, and E3 ligases, in contrast to the removal of ubiquitin, which is accomplished by a series of deubiquitinating enzymes. Regulation of the activity of these enzymes modulates ubiquitin-related pathways and activities [1-4].
Ubiquitination usually marks proteins for proteasomal degradation, and in addition, ubiquitination can be involved in regulatory processes such as protein localization, enzyme activity, and protein-protein interactions [3-4]. Whether a protein is monoubiquitinated or polyubiquitinated, and the type of ubiquitin linkage that forms the polyubiquitin chain, can have different effects on protein function [4-5]. There is growing evidence that ubiquitin may have extracellular functions, and that extracellular ubiquitin regulates cell growth and apoptosis, induces antimicrobial activity and modulates immune responses [6-15]. In addition, ubiquitin is known to inhibit the production of the pro-inflammatory cytokine TNF-α and enhance the production of IL-4, IL-10 and IL-13 [10-15]. However, the mechanisms underlying these effects are unclear.
The study by Saini and colleagues provides evidence that ubiquitin has the ability to activate membrane receptors. Fluorescently labeled ubiquitin exhibits typical receptor binding characteristics. In addition, exogenous ubiquitin can stimulate the receptor and activate cellular response features, including Ca2+?flux, reduction of intracellular cAMP, and downstream phosphorylation of RSK1, Akt, and ERK1/2. The ubiquitin receptor was postulated to be CXCR4 by a combination of bioassays, pharmacology, siRNA knockdown and receptor competition assays [16-18].
CXCR4 is a G protein-coupled receptor known for mediating the activity of the chemokine CXCL12/SDF-1, a potent leukocyte chemotactic agent. CXCR4 also binds to macrophage migration inhibitory factor (MIF), acts as a CD4 co-receptor for HIV-1, and, through its effects on cell motility, cell survival, and angiogenic effects, contributing to advances in cancer research. In many respects, the in vitro biological activities of CXCL12 and ubiquitin are similar. Both stimulate Gαi/o activation, promote Ca2+?movement, and induce similar kinase phosphorylation. Both proteins have also been shown to induce chemotaxis in vitro, although ubiquitin is slightly less potent. In addition, CXCR4 inhibitors block ubiquitin- and CXCL12-induced kinase signaling and effects on cell motility. While there are many similarities between the two, there are also some differences. As an example, CXCL12 and ubiquitin exert their activities through interactions with CXCR4. CXCL12-induced signaling requires an initial interaction with the N-terminal region of CXCR4 followed by binding to the extracellular loop. Unlike ubiquitin, which binds to the same extracellular loop, binding to the N-terminus is not required. Furthermore, unlike CXCL12, ubiquitin does not interfere with HIV-1 binding to CXCR4 and does not have the ability to inhibit infectivity [18-21].
There is a growing interest in ubiquitin activity. Although initially defined as an extracellular factor, most studies have focused on its intracellular role. The identification of CXCR4 as a physiological receptor for ubiquitin would provide a new avenue for research, such as establishing the potential mechanisms by which extracellular ubiquitin affects immune system function?[9-15].
References
1.?Ozkaynak, E. et al. (1984) Nature 312:663.
2.?Goldstein, G. et al. (1975) Proc. Nat. Acad. Sci. USA 72:11.
3.?Ben-Neriah, Y. (2002) Nat. Immunol. 3:20.
4.?Schnell, J.D. & L. Hicke (2003) J. Biol. Chem. 278:35857.
5.?Behrends, C. & J.W. Harper (2011) Nat. Struct. Mol. Biol. 18:520.
6.?Daino, H. et al. (2000) Blood 95:2577.
7.?Singh, M. et al. (2010) Cardiovasc. Res. 86:20.Cites the use of R&D Systems Products
8.?Kieffer, A.E. et al. (2003) FASEB J. 17:776.
9.?Nakamura, M. et al. (1996) J. Immunol. 156:533.
10.?Majetschak, M. et al. (2003) Blood 101:1882.Cites the use of R&D Systems Products
11.?Majetschak, M. et al. (2004) Surgery 135:536.Cites the use of R&D Systems Products
12.?Majetschak, M. et al. (2004) J. Trauma 56:991.Cites the use of R&D Systems Products
13.?Patel, M.B. et al. (2006) J. Surg. Res. 135:226.
14.?Garcia-Covarrubias, L. et al. (2008) Crit. Care Med. 36:979.
15.?Majetschak, M. (2011) J. Leukoc. Biol. 89:205.
16.?Saini, V. et al. (2010) J. Biol. Chem. 285:15566.Cites the use of R&D Systems Products
17.?Saini, V. et al. (2010) Commun. Integr. Biol. 3:608.
18.?Saini, V. et al. (2010) J. Biol. Chem. 286:33466.Cites the use of R&D Systems Products
19.?Busillo, J.M. & J.L. Benovic (2007) Biochim. Biophys. Acta. 1768:952.
20.?Teicher, B.A. & S.P. Fricker (2010) Clin. Cancer Res. 16:2927.
21.?Bernhagen, J. et al. (2007) Nat. Med. 13:587.Cites the use of R&D Systems Products
危险品化学品经营许可证（带存储）