Project description:Reducing sugars can covalently react with proteins to generate a heterogeneous and complex group of compounds called advanced glycation end products (AGEs). AGEs are generally considered as pathogenic molecules, mediating a pro-inflammatory response and contributing to the development of a number of human diseases. However, the intrinsic function of AGEs remains to be elucidated. We now provide multiple lines of evidence showing that AGEs can specifically bind a cell-surface protein and regulate its functions. To identify cellular binding partners for AGEs, we used dehydroascorbic acid (DHA)-modified serum albumins as one of the AGEs to screen for binding proteins in the lipid raft fraction prepared from mouse splenocytes and identified histone localized on the cell-surface as an AGE-binding protein. Histone ubiquitously recognized AGEs, including proteins modified with glucose and its metabolites. AGEs inhibited the binding of plasminogen to the histone component H2B which functions as a cell-surface plasminogen receptor on monocytes/macrophages. Moreover, AGEs regulated the recruitment of monocytes/macrophage to the site of inflammation. Our discovery of histone as a cell-surface receptor for AGEs suggests that, beside our common concept of AGEs as danger-associated molecular patterns mediating a pro-inflammatory response, they may also be involved in the homeostatic response via binding to histone.
Project description:C1QTNF4 is a secreted protein that is structurally unique within the C1QTNF family, a family of proteins that have structural homology with both complement C1q and the tumor necrosis factor superfamily. The role of C1QTNF4 in immunity and inflammation remains poorly defined and a cell surface receptor has yet to be identified. Here we performed co-immunoprecipitation with subsequent mass spectrometric analysis in order to identify a cell surface receptor of C1QTNF4. We report identification of nucleolin as a cell surface binding partner of C1QTNF4. Nucleolin may serve as a docking molecule for C1QTNF4 and act in a context-dependent manner through co-receptors. Having identified nucleolin as a cell surface receptor is a further step to understanding C1QTNF4’s function in the healthy immune system.
Project description:Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Determine the role of LSD1 in androgen signaling.
Project description:Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity, but gains its histone deacetylation function from stable association with the conserved deacetylase activation domain (DAD) contained in nuclear receptor corepressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Remarkably, the NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor corepressors are required for HDAC3 enzyme activity in vivo, and suggest that a deacetylase-independent function of HDAC3 may be required for life. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.