Structural and functional basis for p38-MK2 activated Rsk signalling in Toll-Like receptor-stimulated dendritic cells

Rsk kinases play important roles in several cellular processes such as proliferation, metabolism and migration. Until recently Rsk activation was thought to be exclusively initiated by Erk1/2 but in dendritic cells (DC) Rsk is also activated by p38 MAP kinase via its downstream substrates, MK2/3. How and why this non-canonical configuration of the MAP kinase pathway is adopted by these key immune cells is not known. We demonstrate that Erk1/2-activated C-terminal kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that, compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the non-canonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with TLR7 agonists, Erk1/2 activation is very weak relative to p38. As a result Rsk activation is entirely p38-dependent. We show that this unusual configuration of MAP kinase signalling contributes substantially to production of type I interferons, a hallmark of pDC activation.