ulator. Therefore, YB-1 is needed for IL-6 mRNA production to protect against microbial infection. Moreover, YB-1 is involved in maintaining intracellular IL-6 mRNA levels to prevent a hyperactive immune response. These distinct functions are dependent on the subcellular distribution of YB-1. Depending on the context of cell type-dependent YB-1 function, our data imply that there may be potential relevance to the differences in YB-1 function between the inflammatory infiltrating macrophages and tissue-resident macrophages during various immune responses. 6 SKI-II site Functional Role of YB-1 in Controlling Intracellular IL-6 mRNA Levels Several reports have documented different post-translational modifications for YB-1, including fragmentation, acetylation, and phosphorylation. Interestingly, we show that secretion of YB-1 is dependent on cell type, and that the molecular mass of intracellular and extracellular YB-1 is quite different. The molecular mass of intracellular YB-1 is mostly detectable at,50 kDa, whereas the majority 
of extracellular YB-1 exhibits a size of approximately 37 kDa, along with several other molecular weight species. Previous reports have shown that YB-1 is cleaved by the 20S proteasome, which allows its truncated form to translocate to the nucleus, resulting in more efficient protection of cells from DNA damage. In particular, the 18-kDa fragment of secreted YB-1 was detected in the plasma of cancer patients and we also show the 18 kDa fragment in TCAprecipitated extracellular supernatant from LPS-stimulated macrophages. Therefore, it is possible that the various YB-1 fragments that form in response to LPS may result in altered subcellular localization and immunological function. Furthermore, YB-1 acetylation is required for its secretion. Our results show that YB-1 is acetylated in LPS-stimulated Functional Role of YB-1 in Controlling Intracellular IL-6 mRNA Levels macrophages, but not in dendritic cells. In addition, we demonstrate that HDAC6 expressions differ in a cell typedependent manner, indicating that differences in YB-1 secretion between macrophages and dendritic cells may be correlated with differential HDAC6 expression. In addition, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19692133 during the early phase of inflammation, YB-1 is phosphorylated at Ser102, a site located in the highly conserved cold-shock domain. In addition, calcineurin-mediated YB-1 dephosphorylation regulates CCL5 expression during monocyte differentiation. Because YB-1 contains several possible sites for phosphorylation, it may be possible that LPS regulates YB-1 phosphorylation, leading to changes in its subcellular localization. YB-1 can function as a negative or positive regulator on RNA metabolism. For example, heterozygous YB-1 knockout mice show increased basal expression levels of PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19691363 CXCL1 in the kidney and liver, whereas LPS stimulation results in decreased CXCL1 expression in these organs. Interestingly, the peritoneal lavage fluid of these mice treated with LPS contains elevated CXCL1 levels as compared with wild-type mice. Our study also shows that YB-1 exhibits different functions depending on the cell type, capable of controlling intracellular IL-6 mRNA levels through export or enhancement of stability. Several types of extracellular RNAs have been described. Recent studies have shown that microRNAs are released and that secretory miRNAs are transferable by packaged Functional Role of YB-1 in Controlling Intracellular IL-6 mRNA Levels vesicles and functional in recipient cells. It is
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