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

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

doi:10.1172/jci.insight.121144

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

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

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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.

Original language	English
Pages (from-to)	1-17
Journal	JCI Insight
Volume	3
Issue number	16
Early online date	23 Aug 2018
DOIs	https://doi.org/10.1172/jci.insight.121144
Publication status	Published - 23 Aug 2018

Keywords

Cardiology
Pharmacology
Protein kinases
Structural biology
Therapeutics

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10.1172/jci.insight.121144Licence: CC BY

The TAB1-p38α complex_DE NICOLA_Accepted5July2018_GOLD VoR (CC BY)Final published version, 3.41 MBLicence: CC BY

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De Nicola, G. F., Bassi, R., Nichols, C., Fernandez-Caggiano, M., Golforoush, P. A., Thapa, D., Anderson, R., Martin, E. D., Verma, S., Kleinjung, J., Laing, A., Hutchinson, J. P., Eaton, P., Clark, J., & Marber, M. S. (2018). The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules. JCI Insight, 3(16), 1-17. https://doi.org/10.1172/jci.insight.121144

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title = "The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules",

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.",

keywords = "Cardiology, Pharmacology, Protein kinases, Structural biology, Therapeutics",

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

year = "2018",

month = aug,

day = "23",

doi = "10.1172/jci.insight.121144",

language = "English",

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De Nicola, GF , Bassi, R, Nichols, C, Fernandez-Caggiano, M, Golforoush, PA, Thapa, D , Anderson, R , Martin, ED , Verma, S, Kleinjung, J, Laing, A, Hutchinson, JP, Eaton, P , Clark, J & Marber, MS 2018, 'The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules', JCI Insight, vol. 3, no. 16, pp. 1-17. https://doi.org/10.1172/jci.insight.121144

TY - JOUR

T1 - The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules

AU - De Nicola, Gian F.

AU - Bassi, Rekha

AU - Nichols, Charlie

AU - Fernandez-Caggiano, Mariana

AU - Golforoush, Pelin Arabacilar

AU - Thapa, Dibesh

AU - Anderson, Rhys

AU - Martin, Eva Denise

AU - Verma, Sharwari

AU - Kleinjung, Jens

AU - Laing, Adam

AU - Hutchinson, Jonathan P.

AU - Eaton, Philip

AU - Clark, James

AU - Marber, Michael S.

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 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.

AB - 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.

KW - Cardiology

KW - Pharmacology

KW - Protein kinases

KW - Structural biology

KW - Therapeutics

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U2 - 10.1172/jci.insight.121144

DO - 10.1172/jci.insight.121144

M3 - Article

C2 - 30135318

SN - 2379-3708

VL - 3

SP - 1

EP - 17

JO - JCI Insight

JF - JCI Insight

IS - 16

ER -

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

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