title: Tid1, the Mammalian Homologue of Drosophila Tumor Suppressor Tid56, Mediates Macroautophagy by Interacting with Beclin1-containing Autophagy Protein Complex.
abstract: One of the fundamental functions of molecular chaperone proteins is to selectively conjugate cellular proteins, targeting them directly to lysosome. Some of chaperones, such as the stress-induced Hsp70, also play important roles in autophagosome-forming macroautophagy under various stress conditions. However, the role of their co-chaperones in autophagy regulation has not been well defined. We here show that Tid1, a DnaJ co-chaperone for Hsp70 and the mammalian homologue of the Drosophila tumor suppressor Tid56, is a key mediator of macroautophagy pathway. Ectopic expression of Tid1 induces autophagy by forming LC3+ autophagosome foci, whereas silencing Tid1 leads to drastic impairment of autophagy as induced by nutrient deprivation or rapamycin. In contrast, Hsp70 is dispensable for a role in nutrient deprivation-induced autophagy. The murine Tid1 can be replaced with human Tid1 in murine fibroblast cells for induction of autophagy. We further show that Tid1 increases autophagy flux by interacting with the Beclin1-PI3 kinase class III protein complex in response to autophagy inducing signal and that Tid1 is an essential mediator that connects IκB kinases to the Beclin1-containing autophagy protein complex. Together, these results reveal a crucial role of Tid1 as an evolutionarily conserved and essential mediator of canonical macroautophagy.
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Ge
authors.initials: G
authors.lastname: Niu
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Chandra
authors.initials: C
authors.lastname: Belani
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: hcheng@ihv.umaryland.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D002460:Cell Line; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins; D060066:Protein Interaction Maps
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C093721:CG5504 protein, Drosophila; C120664:DNAJA3 protein, human; D029721:Drosophila Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051550:I-kappa B Kinase
keywords: 70 kilodalton heat shock protein (Hsp70); Beclin-1 (BECN1); PI3KC3; Tid1; autophagy; chaperone DnaJ (DnaJ); molecular chaperone