Defects in MAP1S-mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Wenjiao Li, Jing Zou, Fei Yue, Kun Song, Qi Chen, Wallace L. Mckeehan, Fen Wang, Guibin Xu, Hai Huang, Jinglin Yi, Leyuan Liu

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Autophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule-associated protein MAP1S interacts with autophagy marker LC3 and positively regulates autophagy flux. LC3 binds with fibronectinmRNA 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 MAP1S-mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC3 in wild-type mice increases the levels of fibronectin and γ-H2AX, a marker of DNA double-strand breakage. LC3-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 LC3 transgenic mice with MAP1S deleted, LC3 enhances the synthesis of fibronectin but the MAP1S 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 LC3-induced overexpression of fibronectin imposes stresses on MAP1S-deficient mice and dramatically reduces their lifespans. Therefore, MAP1S-mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin.

Original languageEnglish (US)
Pages (from-to)370-379
Number of pages10
JournalAging Cell
Volume15
Issue number2
DOIs
StatePublished - Apr 1 2016

Keywords

  • Autophagy
  • Fibronectin
  • Lifespan
  • Liver fibrosis
  • MAP1S

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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