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Lee JH, Park SM, Kim OS, Lee CS, Woo JH, Park SJ, Joe EH, Jou I. Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes. Mol Cell. 2009 Sep 24;35(6):806-17. PubMed.
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University of Pittsburgh
In this article, Lee et al. examine the mechanism by which Liver X Receptors (LXRα /b) inhibit inflammation in astrocytes. LXR are key transcriptional regulators of cholesterol and lipid metabolism, and LXR agonists were shown to decrease amyloid deposition in APP transgenic mice (1-3). LXR ligands, and thus activated LXR, inhibit inflammation in the periphery as well as in the brain, but how they do that was a mystery (4,5).
In this study, the authors use primary astrocytes from rat brain that were stimulated by IFN-g to produce inflammatory cytokines. Lee et al. concentrate on signal transduction activity and enhancement of transcription (STAT1) signaling pathways. First, they prove that LXR ligands do not affect the phosphorylation or nuclear translocation of STAT1, but rather prevent its binding to the promoter. Next, using a series of elegant and convincing experiments, Lee et al. prove that the suppressive actions of LXR ligands on STAT1 inflammatory signaling are LXR-receptor dependent. It means that LXRα and LXRβ use slightly different but still similar ways to inhibit STAT1, which is very unexpected. The similarity is in the inhibition of STAT1 caused by SUMOylation of LXRα and LXRβ . The authors found a difference as well—the SUMOylation was mediated through different SUMO E ligases. LXRα was SUMOylated by HDAC4, which is both a SUMO E3 ligase and a histone deacetylase, and LXRβ by PIAS1, which is another SUMO 3 ligase. This is a very interesting finding and, as the authors state, the specific regulation of LXRα and LXRβ through SUMOylation can be exploited therapeutically in Alzheimer disease and stroke.
References:
Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008 Jun 12;58(5):681-93. PubMed.
Koldamova R, Lefterov I. Role of LXR and ABCA1 in the pathogenesis of Alzheimer's disease - implications for a new therapeutic approach. Curr Alzheimer Res. 2007 Apr;4(2):171-8. PubMed.
Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease. J Biol Chem. 2005 Feb 11;280(6):4079-88. PubMed.
Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R. Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener. 2007;2:20. PubMed.
Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10601-6. PubMed.
Centre de recherche du CHUL (CHUQ)
The present study assesses the control of inflammatory signaling by SUMOylation of nuclear receptors in immunity. LXRα/β are ligand-activated nuclear receptors that can inhibit the expression of inflammatory genes. It is known that inflammation contributes to several human pathologies, including Alzheimer disease (AD). SUMOylation is a post-translational modification, and the interest for the identification of substrates and functions keep growing. It has been shown that tau, involved in AD neurofibrillary tangles, is a SUMO substrate. And a fast-growing number of SUMO substrates are identified in healthy and disease neurons. Here, Lee and colleagues demonstrate a new link between SUMO and inflammation.
Using rat brain astrocytes, the authors showed that the expression of STAT1-regulated inflammatory genes is negatively regulated by the formation of the trimeric complexes HDAC4/STAT1/LXRα and PIAS1/STAT1/LXRβ. PIAS1 and HDAC4 are known SUMO ligases, and in addition to their presence in the complexes, the authors showed that LXRs are SUMOylated in the trimers. These complexes cannot bind to genes promoters, inhibiting the expression of inflammatory genes. A role for SUMO in this nuclear processing is not surprising. It is one of the major, not exclusive, role of SUMOylation.
The specificity between SUMOylation of LXRα by SUMO2 and LXRβ by SUMO1 is puzzling and not addressed in the present paper. SUMO2 and SUMO3 share 95 percent sequence homology, and the specificity of SUMO2, as compared to SUMO3, has not been taken into consideration. Interesting future studies will likely include the crosstalk between both LXRs, the effect of different stimulating ligands, and the crosstalk with other inflammatory signaling pathways.
Overall, this is an interesting paper and adds to a better understanding of the regulation of inflammation. It can lead to the development of new therapeutic avenues that would benefit uncontrolled inflammatory pathogeneses, including Alzheimer disease. Of course, this is not in the near future, but the research should be exploited.
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