Defects in MAP 1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Summary Autophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule‐associated protein MAP 1S interacts with autophagy marker LC 3 and positively regulates autophagy flux. LC 3 binds with fibronectin mRNA and facilitates its translation. The synthesized fibronectin protein is exported to cell surface to initiate the assembly of fibronectin extracellular matrix. Fibronectin is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here, we show that defects in MAP 1S‐mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC 3 in wild‐type mice increases the levels of fibronectin and γ‐H 2 AX , a marker of DNA double‐strand breakage. LC 3‐induced fibronectin is efficiently degraded in lysosomes to maintain a balance of fibronectin levels in wild‐type mice so that the mice live a normal term of lifespan. In the LC 3 transgenic mice with MAP 1S deleted, LC 3 enhances the synthesis of fibronectin but the MAP 1S depletion causes an impairment of the lysosomal degradation of fibronectin. The accumulation of fibronectin protein promotes liver fibrosis, induces an accumulation of cell population at the G0/G1 stage, and further intensifies oxidative stress and sinusoidal dilatation. The LC 3‐induced overexpression of fibronectin imposes stresses on MAP 1S‐deficient mice and dramatically reduces their lifespans. Therefore, MAP 1S‐mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin.