E-MTAB-6460
The TAB1-p38a complex aggravates myocardial injury and can be targeted by small molecules
There is considerable evidence that inhibition of p38a mitogen-activated protein kinase diminishes cardiac damage during myocardial ischemia. During myocardial ischemia p38a interacts with TAB1, a scaffold protein, which promotes p38a autoactivation; active p38a (pp38a) then trans-phosphorylates TAB1.  Previously, we solved the X-ray structure of the p38a-TAB1(384-412) complex. Here we further characterize the interaction by resolving the structure of the pp38a-TAB1(1-438) complex in the active state. Based on this information we created a global knock-in mouse with substitution of four residues on TAB1 (V390A, Y392A, V408G, M409A) we show are required for docking onto p38a. Whereas ablating p38a or TAB1 results in early embryonal lethality, the TAB1 KI mice are viable, develop normally and have no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile. Nonetheless, following in vivo regional myocardial ischemia, infarction volume is significantly reduced and the trans- phosphorylation of TAB1 is disabled. Unexpectedly, the activation of myocardial p38a during ischemia is only mildly attenuated in TAB1 KI hearts, an effect most likely due to the removal of the steric hindrance to MAP2K3 binding. We conclude that it is the phosphorylation of TAB1 by pp38a during ischemia that is associated with cardiac damage.  The data reveal that it is possible to selectively inhibit signalling downstream of p38a to attenuate ischemic injury. Our findings validate the p38a-TAB1 complex as a therapeutic target that may circumvent the toxicity associated with ATP-competitive inhibitors of p38a.
There is considerable evidence that inhibition of p38a mitogen-activated protein kinase diminishes cardiac damage during myocardial ischemia. During myocardial ischemia p38a interacts with TAB1, a scaffold protein, which promotes p38a autoactivation; active p38a (pp38a) then trans-phosphorylates TAB1.  Previously, we solved the X-ray structure of the p38a-TAB1(384-412) complex. Here we further characterize the interaction by resolving the structure of the pp38a-TAB1(1-438) complex in the active state. Based on this information we created a global knock-in mouse with substitution of four residues on TAB1 (V390A, Y392A, V408G, M409A) we show are required for docking onto p38a. Whereas ablating p38a or TAB1 results in early embryonal lethality, the TAB1 KI mice are viable, develop normally and have no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile. Nonetheless, following in vivo regional myocardial ischemia, infarction volume is significantly reduced and the trans- phosphorylation of TAB1 is disabled. Unexpectedly, the activation of myocardial p38a during ischemia is only mildly attenuated in TAB1 KI hearts, an effect most likely due to the removal of the steric hindrance to MAP2K3 binding. We conclude that it is the phosphorylation of TAB1 by pp38a during ischemia that is associated with cardiac damage.  The data reveal that it is possible to selectively inhibit signalling downstream of p38a to attenuate ischemic injury. Our findings validate the p38a-TAB1 complex as a therapeutic target that may circumvent the toxicity associated with ATP-competitive inhibitors of p38a.