Sprouty2 modulates NF-κB signaling by sequestering the phosphatase PP2Ac in LPS-stimulated macrophages.

The role of the adapter protein Sprouty2 (Spry2) in lipopolysaccharide (LPS)/TLR4-mediated signaling is unknown. In the present study we show that Spry2 positively regulates NF-κB signaling by sequestering the negative regulator PP2Ac in LPS-stimulated bone marrow derived macrophages (BMDM). Spry2 deficient BMDM display impaired LPS/TLR4-induced cytokine production and NF-κB activation. This impaired cytokine production in Spry2 deficient macrophages is not due to defects in receptor proximal signaling events or dysregulated MAPK activation. Mechanistically, we show that upon LPS stimulation, Spry2 is serine phosphorylated and associated with the phosphatase PP2Ac. The PP2Ac sequestration by Spry2 heightens NF-κB activation, enhances nuclear translocation of p65 and augments cytokine production. On the other hand, macrophages from Spry2 deficient mice display enhanced interaction between PP2Ac and p65, increased p65 dephosphorylation, reduced nuclear translocation of p65 and curtailed cytokine secretion. Pretreatment of Spry2 deficient macrophages with PP2Ac inhibitors restores p65 nuclear translocation and cytokine secretion in response to LPS. Collectively, our study suggest a novel role for Spry2 in modulation of NF-κB activation in response to LPS.