title: Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide.
abstract: Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many autophagy genes. Here, we show that, in contrast to Fip200 deletion, inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 does not impair the maintenance and differentiation of postnatal neural stem cells (NSCs). Only Fip200 deletion, but not Atg5, Atg16L1, or Atg7 deletion, caused p62/sequestome1 aggregates to accumulate in NSCs. Fip200 and p62 double conditional knockout mice demonstrated that p62 aggregate formation triggers aberrant superoxide increases by impairing superoxide dismutase functions. By comparing the inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 with Fip200 deletion, we revealed a critical role of increased p62 in determining the fate of autophagy-deficient NSCs through intracellular superoxide control.
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
authors.forename: Chenran
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
authors.forename: Syn
authors.initials: S
authors.lastname: Yeo
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903.
authors.forename: Gizem
authors.initials: G
authors.lastname: Karsli-Uzunbas
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903.
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63310.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 guanjl@uc.edu.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D006360:Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D013481:Superoxides / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D013481:Superoxides