title: Defects in MAP1S-mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed.
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-H2 AX, 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.
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.|Department of ophthalmology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Jiangxi Research Institute of Ophthalmology and Visual Sciences, The Affiliated Eye Hospital of Nanchang University, Nanchang, 330006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yue
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Song
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Wallace L
authors.initials: WL
authors.lastname: McKeehan
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Guibin
authors.initials: G
authors.lastname: Xu
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.|Department of Urology, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Jiangxi Research Institute of Ophthalmology and Visual Sciences, The Affiliated Eye Hospital of Nanchang University, Nanchang, 330006, China.
authors.forename: Jinglin
authors.initials: J
authors.lastname: Yi
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.|Jiangxi Research Institute of Ophthalmology and Visual Sciences, The Affiliated Eye Hospital of Nanchang University, Nanchang, 330006, China.|Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, 77843, USA.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D005353:Fibronectins; C570460:MAP1S protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins
keywords: MAP1S; autophagy; fibronectin; lifespan; liver fibrosis