Tumor suppressor death-associated protein kinase 1 inhibits necroptosis by p38 MAPK activation

Abstract

Death-associated protein kinase 1 (DAPK1, DAPk, DAPK) is known for its involvement in apoptosis and autophagyassociated cell death. Here, we identified an unexpected function of DAPK1 in suppressing necroptosis. DAPK1deficiency renders macrophages and dendritic cells susceptible to necroptotic death. We also observed an inhibitory role for DAPK1 in necroptosis in HT-29 cells, since knockdown or knockout of DAPK1 in such cells increased their sensitivity to necroptosis. Increased necroptosis was associated with enhanced formation of the RIPK1-RIPK3-MLKL complex in these DAPK1-deficient cells. We further found that DAPK1-deficiency led to decreased MAPK activated kinase 2 (MK2) activation and reduced RIPK1 S321 phosphorylation, with this latter representing a critical step controlling necrosome formation. Most TNF signaling pathways, including ERK, JNK, and AKT, were not regulated by DAPK. In contrast, DAPK bound p38 MAPK and selectively promoted p38 MAPK activation, resulting in enhanced MK2 phosphorylation. Our results reveal a novel role for DAPK1 in inhibiting necroptosis and illustrate an unexpected selectivity for DAPK1 in promoting p38 MAPK-MK2 activation. Importantly, our study suggests that modulation of necroptosis and p38/MK2-mediated inflammation may be achieved by targeting DAPK1.

Diversity and versatility of p38 kinase signalling in health and disease

“… 47 ); and binding to DAPK1 that enhances p38α phosphorylation by MKK3 (ref. 48 ). Post-translational modifications other than phosphorylation further modulate p38α activity, including acetylation of Lys53 that enhances activity by promoting ATP binding 49 , isomerization of Pro224 that facilitates MAP2K-mediated phosphorylation 50 or arginine methylations that promote particular p38α functions 51 , 52 (Fig.…”

Roles of necroptosis in alcoholic liver disease and hepatic pathogenesis

“…DAPK1 binds with p38 (MAPK) and promotes its activation, which leads to elevated phosphorylation of MK2, resulting in the suppression of necroptosis. 48 Together, the above researches illustrate that MK2 inhibits necroptosis through phosphorylating RIPK1 on S321 and S336, with consequently decreased activation of RIPK1 and reduced formation of necrosome.…”

“…In addition, death‐associated protein kinase 1 (DAPK1) is identified as a negative regulator of necroptosis, deficiency of which enhances the formation of the RIPK1‐RIPK3‐MLKL complex, associated with reduced MK2‐mediated phosphorylation of RIPK1 on S321. DAPK1 binds with p38 (MAPK) and promotes its activation, which leads to elevated phosphorylation of MK2, resulting in the suppression of necroptosis 48 . Together, the above researches illustrate that MK2 inhibits necroptosis through phosphorylating RIPK1 on S321 and S336, with consequently decreased activation of RIPK1 and reduced formation of necrosome.…”

Dapk1 promoted inflammation of infantile pneumonia by p38MAPK/NF-κB signaling pathway

“…Furthermore, this study demonstrated that Dapk1 promotes p38MAPK-mediated NF-κB expression to increase in ammation in vitro model of infantile pneumonia. Wu et al reveal that tumor suppressor Dapk1 inhibits necroptosis by p38 MAPK activation (20). NF-κB is an important nuclear transcription factor that regulates the immune response and in ammatory pathways.…”