MAP kinases are involved in RNA polymerase III regulation upon LPS treatment in macrophages

Macrophages are transcriptionally highly dynamic cell type, rapidly adapting to a changing environment to execute innate immune functions. Activation of macrophages with lipopolysaccharides (LPS), a major component of the outer membrane of most Gram-negative bacteria, induces rapid transcriptional changes and within a few hours transcription of several hundred genes is altered. Within these genes are tRNAs, which are synthesised by RNA Polymerase (Pol) III, and whose expression is rapidly upregulated in response to LPS. However, the mechanisms that govern Pol III activation are not fully elucidated. LPS engage the Toll-like receptor (TLR) 4 and induce various signalling pathways, including mitogen-activated protein kinases (MAPK). MAPKs are serine/threonine kinases that catalyse the phosphorylation of transcription factors, protein kinases, and many other substrates including functional proteins, play a central role in mediating cellular responses to extracellular signals, including inflammatory cues. Here we show that ERK and p38 MAP kinases contribute to the activation of Pol III in macrophages stimulated with LPS. We also demonstrate that MAP kinases effector MSK1/2 kinases are involved in tRNA upregulation. Our data show that ERK, p38, and MSK kinases are required for upregulation of Pol III activity in macrophages stimulated by LPS. The possible modes of their action are discussed.