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

Gian F De Nicola,Philip Eaton,Jonathan P Hutchinson,Dibesh Thapa,Sharwari Verma,Rhys Anderson,Rekha Bassi,Adam Laing,Michael S Marber,Jens Kleinjung,Eva Denise Martin,Charlie Nichols,James Clark,Pelin Arabacilar Golforoush,Mariana Fernandez-Caggiano

doi:10.1172/jci.insight.121144

Abstract

Inhibiting MAPK14 (p38α) diminishes cardiac damage in myocardial ischemia. During myocardial ischemia, p38α interacts with TAB1, a scaffold protein, which promotes p38α autoactivation; active p38α (pp38α) then transphosphorylates TAB1. Previously, we solved the X-ray structure of the p38α-TAB1 (residues 384–412) complex. Here, we further characterize the interaction by solving the structure of the pp38α-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 p38α. Whereas ablating p38α 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 p38α during ischemia was only mildly attenuated in TAB1-KI hearts. We also identified a group of fragments able to disrupt the interaction between p38α 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 p38α to attenuate ischemic injury.

Highlights

The MAPK p38α is a serine threonine protein kinase that is activated by stress
Based on the results presented here, we propose that TAB1 phosphorylation downstream of p38α is associated with cardiac damage during ischemia
TAB1 binds to p38α and induces autophosphorylation of residues Thr180 and Tyr182; active p38α is able to phosphorylate TAB1 on residue Serine 423 [13]

Summary

Introduction

The MAPK p38α is a serine threonine protein kinase that is activated by stress. The kinase is expressed in all mammalian cell types and is highly conserved in yeast. Ablating p38α in mice results in early embryonal lethality, and in yeast, it results in failures in adaptation to environmental stress and pheromones. P38α has an essential role in health and homeostasis [1, 2]. In animal models of acute myocardial infarction and heart failure, inhibition of p38α reduces infarct size, improves left ventricular function, and limits cardiac dilatation. Cardiacrestricted forced activation of p38α damages the myocardium. P38α inhibition makes therapeutic sense in ischemic heart disease [3,4,5]

Methods

Results

Conclusion