MAP1S‐enhanced Autophagy Alleviates Tissue Fibrosis and Sustains Mouse Survival under Stress Imposed by LC3‐induced Overexpression of Fibronectin

Abstract

Autophagy is a cellular process that controls and executes the turnover of misfolded and abnormally aggregated proteins. Microtubule‐associated protein 1S (MAP1S) interacts with autophagy marker light chain 3 (LC3) and positively regulates autophagy flux. LC3 also binds with fibronectin mRNA and facilitates its sorting along microtubules onto rough endoplasmic reticulum where it is translated into fibronectin protein. Fibronectin is exported to surface of plasma membrane to initiate the assembly of fibronectin extracellular matrix and other extracellular matrix proteins. Fibronectin matrix is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here we show that overexpression of LC3 in wildtype mice promoted the synthesis and degradation of fibronectin and consequently resulted in a balanced levels of fibronectin; therefore, the GFP‐LC3 transgenic mice had a normal length of lifespan as the wild‐type mice did. In GFP‐LC3 transgenic mice with MAP1S deleted, LC3 overexpression enhanced synthesis of fibronectin while MAP1S‐deficiency‐caused autophagy defect impaired the degradation of fibronectin. The accumulation of fibronectin protein led to enhanced levels of oxidative stress, genomic instability and tissue fibrosis, and to a dramatic 35% reduction in mouse lifespan. Therefore, autophagy may play an important role in maintaining mouse lifespan via regulating the homeostasis of fibronectin extracellular matrix.This work was supported by a NIH R01CA142862 to Leyuan Liu.