Investigation of a translational control mechanism activated by interleukin 1

• Applicant: Professor Dr. Helmut Holtmann
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2010 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 187087359

The pro-inflammatory cytokine IL-1 activates post-transcriptional mechanisms that contribute to the expression of proteins involved in immune and inflammatory reactions. Information obtained in the first funding period indicates that IL-1 increases translation of two distinct groups of mRNAs by counteracting translational silencing mechanisms. One group, represented by mRNAs of IL-6 and IL-1alpha itself, is translationally silenced by KSRP, a protein that interacts with AU-rich elements (AREs) in these mRNAs. The second group, represented by mRNAs of IkappaBzeta and MCPIP1, is silenced independently of KSRP and AREs.Our recent observations suggest that MCPIP1 protein (auto)regulates translation of its own mRNA and that of IkappaBzeta through interaction with these mRNAs. Thus MCPIP1, recently described as an important negative feedback regulator of inflammatory gene expression, is a candidate for regulating the non-ARE group of target mRNAs by IL-1. Importantly, evidence for this kind of regulation was obtained in different cell types and also in response to bacterial lipopolysaccharide and IL-17.To elucidate the molecular mechanism of this kind of translational control, we plan to analyse MCPIP1 function in the context of the translational silencing element of IkappaBzeta mRNA. Key objectives are to obtain information on structural features of MCPIP1 required for translational silencing (including the role of its RNase activity), the interaction of MCPIP1 with other proteins, the modulation of MCPIP1 function by IL-1, and the spectrum of target mRNAs of MCPIP1.The information gained should contribute to closing a gap in our knowledge on post-transcriptional control of gene expression during inflammation.

• DFG Programme: Research Grants