A non-canonical function of eukaryotic elongation factor 1A1: Regulation of interleukin-6 expression

作者：Schulz Ingo; Engel Claudia; Niestroj Andre J; Kehlen Astrid; Rahfeld Jens Ulrich; Kleinschmidt Martin; Lehmann Karola; Rossner Steffen^*; Demuth Hans Ulrich

来源：Biochimica et Biophysica Acta-Molecular Cell Research, 2014, 1843(5): 965-975.

DOI：10.1016/j.bbamcr.2014.01.022

• Eukaryotic elongation factor 1A1
• Interleukin-6
• Protein kinase C delta
• STAT3

Interleulcin-6 is one of the most prominent triggers of inflammatory processes. We have shown recently that heteroarylketones (HAKs) interfere with stimulated interleukin-6 expression in astrocytes by suppression of STAT3 phosphorylation at serine 727. Surprisingly, this effect is not based on the inhibition of STAT3-relevant kinases. Therefore, we here used the structurally modified HAK compound biotin-HAK-3 in a reverse chemical approach to identify the relevant molecular target in UV-mediated cross-linking experiments. Employing streptavidin-specific 2D-immunoblotting followed by mass spectrometry we identified nine proteins putatively interacting with biotin-HAK-3. After co-immunoprecipitation, co-immunofluorescence, surface plasmon resonance analyses and RNAi-mediated knock-down, the eukaryotic elongation factor 1A1 (eEF1A1) was verified as the relevant target of MAR bioactivity. eEF1A1 forms complexes with STAT3 and PKCS, which are crucial for STAT3(S727) phosphorylation and for NF-kappa B/STAT3-enhanced interleukin-6 expression. Furthermore, the intracellular HAK accumulation is strongly dependent on eEF1A1 expression. Taken together, the results reveal a novel molecular mechanism for a non-canonical role of eEF1A1 in signal transduction via direct modulation of kinase-dependent phosphorylation events.

• 出版日期2014-5