首页|LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis

LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis

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The factors that determine fibrosis progression or normal tissue repair are largely unknown.We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EMT)in human alveolar epithelial type Ⅱ(ATⅡ)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signaling.Here,we report that liver kinase B1(LKB1)inactivation in ATⅡ cells inhibits autophagy and induces EMT as a conse-quence.In IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATⅡ cells and MRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATⅡ cells and fibroblasts augmented myofibroblast differentiation.Together,these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATⅡ cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

CAB39LCrosstalkEMTLKB1Pulmonary fibrosis

Zijian Xu、Elizabeth R.Davies、Liudi Yao、Yilu Zhou、Juanjuan Li、Aiman Alzetani、Ben G.Marshall、David Hancock、Tim Wallis、Julian Downward、Rob M.Ewing、Donna E.Davies、Mark G.Jones、Yihua Wang

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Biological Sciences,Faculty of Environmental and Life Sciences,University of Southampton,Southampton SO17 1BJ,UK

Clinical and Experimental Sciences,Faculty of Medicine,University of Southampton,Southampton SO16 6YD,UK

Institute for Life Sciences,University of Southampton,Southampton SO17 1BJ,UK

NIHR Southampton Biomedical Research Centre,University Hospital Southampton,Southampton SO166YD,UK

University Hospital Southampton,Southampton SO16 6YD,UK

Oncogene Biology,The Francis Crick Institute,London NW1 1AT,UK

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UK Medical Research CouncilUK Academy of Medical sciences/the Wellcome Trust Springboard AwardAAIR Charity国家留学基金委项目Institute for Life Sciences PhD StudentshipFrancis Crick Institute which receives its core funding from Cancer Research UK

MR/S025480/1SBF002\1038FC001070

2024

10.1016/j.gendis.2023.06.034

基因与疾病(英文)

基因与疾病(英文)

ISSN：
年,卷(期)：2024.11(3)
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