Hippo kinase NDR2 inhibits IL-17 signaling by promoting Smurf1-mediated MEKK2 ubiquitination and degradation

Abstract NDR/LATS kinase family are conserved from yeast to man and their roles in inflammation remains largely unknown. In the present study, we show that knockdown of NDR2 significantly increases IL-17-induced IL-6, CXCL2 and CCL20 expression in Hela and HT-29 cells. Knockdown of NDR2 enhances IL-17-induced MAPK and NF-κB activation. NDR2 interacts with E3 ubiquitin protein ligase Smurf1, promotes Smurf1-mediated K48-linked ubiquitination of MEKK2 and inhibits expression of MEKK2. Consistently, knockdown of Smurf1 increases IL-17-induced IL-6, CXCL2 and CCL20 expression. On the other hand, overexpression of MEKK2 increases IL-17-induced IL-6 expression. These results suggest that NDR2 may play important roles in IL-17-associated inflammation by promoting Smurf1-mediated MEKK2 ubiquitination and degradation.