The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules.

Inhibiting MAPK14 (p38 alpha) diminishes cardiac damage in myocardial ischemia. During myocardial ischemia, p38 alpha interacts with TAB1, a scaffold protein, which promotes p38 alpha autoactivation; active p38 alpha (pp38 alpha) then transphosphorylates TAB1. Previously, we solved the X-ray structure of the p38 alpha-TAB1 (residues 384-412) complex. Here, we further characterize the interaction by solving the structure of the pp38 alpha-TAB1 (residues 1-438) complex in the active state. Based on this information, we created a global knock-in (KI) mouse with substitution of 4 residues on TAB1 that we show are required for docking onto p38 alpha. Whereas ablating p38 alpha or TAB1 resulted in early embryonal lethality, the TAB1-KI mice were viable and had no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile; nonetheless, following in vivo regional myocardial ischemia, infarction volume was significantly reduced and the transphosphorylation of TAB1 was disabled. Unexpectedly, the activation of myocardial p38 alpha during ischemia was only mildly attenuated in TAB1-KI hearts. We also identified a group of fragments able to disrupt the interaction between p38 alpha and TAB1. We conclude that the interaction between the 2 proteins can be targeted with small molecules. The data reveal that it is possible to selectively inhibit signaling downstream of p38 alpha to attenuate ischemic injury.