p38γ and p38δ modulate innate immune response by regulating MEF2D activation

Escós, Alejandra; Diaz-Mora, Ester; Pattison, Michael J.; Fajardo, Pilar; González-Romero, Diego; Risco, Ana Marı́a; Martín-Gómez, José Javier; Bonneil, Eric; Sonenberg, Nahum; Jafarnejad, Seyed Mehdi; Sanz‐Ezquerro, Juan José; Ley, Steven C.; Cuenda, Ana

doi:10.1101/2022.12.09.519777

Cited by 1 publication

(1 citation statement)

References 34 publications

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“…First, an important premise of the present study was that the definition of MAPK13 function remained incomplete despite previous studies of MAPK13 deficiency in gene-knockout mice. Some of the uncertainty was due to the frequent performance of MAPK13 studies in combination with MAPK12 deficiency, based on the similar protein sequence/structure and in some cases tissue distribution of these two potentially redundant kinases (27,(47)(48)(49)(50)(51)(52)(53). Given the present results, it is rational to consider the function of MAPK13 on its own.…”

Section: Discussionmentioning

confidence: 84%

MAPK13 controls structural remodeling and disease after epithelial injury

Wu,

Zhang,

Mao

et al. 2024

Preprint

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All living organisms are charged with repair after injury particularly at epithelial barrier sites, but in some cases this response leads instead to structural remodeling and long-term disease. Identifying the molecular and cellular control of this divergence is key to disease modification. In that regard, stress kinase control of epithelial stem cells is a rational entry point for study. Here we examine the potential for mitogen-activated protein kinase 13 (MAPK13) regulation of epithelial stem cells using models of respiratory viral injury and post-viral lung disease. We show thatMapk13gene-knockout mice handle acute infectious illness as expected but are protected against structural remodeling manifest as basal-epithelial stem cell (basal-ESC) hyperplasia-metaplasia, immune activation, and mucinous differentiation. In corresponding cell models,Mapk13-deficiency directly attenuates basal-ESC growth and organoid formation. Extension to human studies shows marked induction/activation of basal-cell MAPK13 in clinical samples of comparable remodeling found in asthma and COPD. Here again,MAPK13gene-knockdown inhibits human basal-ESC growth in culture. Together, the data identify MAPK13 as a control for structural remodeling and disease after epithelial injury and as a suitable target for down-regulation as a disease-modifying strategy.New and noteworthyThis study identifies a distinct role for stress kinase MAPK13 in controlling the epithelial stem cell response to injury and the consequent development of tissue remodeling. The present model has direct implications for lung injury and subsequent disease triggered by respiratory viruses and other inhaled toxins, but the broad distribution of MAPK13 implies related actions at other barrier and tissue sites. The findings also refine a hypothesis for therapeutic intervention based on proper scaling of MAPK13 function including down-regulation with selective kinase inhibitors.

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