MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
Authors: Romero-Becerra Rafael , Mora Alfonso , Manieri Elisa , Sanz Laura , Nikolic Ivana , Santamans Ayelén M. , Montalvo-Romeral Valle , Cruz Uréndez Francisco Miguel , Rodríguez Maria Elena , Leiva-Vega Luis , Bondía Víctor , Filgueiras-Rama David , Jiménez-Borreguero Luis Jesús , Jalife José , González-Terán Bárbara , Sabio Guadalupe 
Published: November 2021

ABSTRACTStress-activated p38 kinases control a plethora of functions and their dysregulation has been linked to development of steatosis, obesity, immune disorders and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here we demonstrate that lack of MKK6 reduces the life span in mice. Longitudinal study of cardiac function in Mkk6-/- mice showed that young mice have cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mTOR signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in Mkk6-/- mice is reverted by knocking out either p38γ or p38δ, or by inhibiting mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.eLife’s Review ProcesseLife works to improve the process of peer review so that it more effectively conveys the assessment of expert reviewers to authors, readers and other interested parties. In the future we envision a system in which research is first published as a preprint and the outputs of peer review are the primary way research is assessed, rather than journal title.Our editorial process produces two outputs: i) an assessment by peers designed to be posted alongside a preprint for the benefit of the readers; ii) detailed feedback on the manuscript for the authors, including requests for revisions and suggestions for improvement.Therefore we want to change how we construct and write peer reviews to make them useful to both authors and readers in a way that better reflects the work you put into reading and thinking about a paper.eLife reviews now have three parts:
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