title: The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis.
abstract: ULK1 and ULK2 are thought to be essential for initiating autophagy, and Ulk1/2-deficient mice die perinatally of autophagy-related defects. Therefore, we used a conditional knockout approach to investigate the roles of ULK1/2 in the brain. Although the mice showed neuronal degeneration, the neurons showed no accumulation of P62(+)/ubiquitin(+) inclusions or abnormal membranous structures, which are observed in mice lacking other autophagy genes. Rather, neuronal death was associated with activation of the unfolded protein response (UPR) pathway. An unbiased proteomics approach identified SEC16A as an ULK1/2 interaction partner. ULK-mediated phosphorylation of SEC16A regulated the assembly of endoplasmic reticulum (ER) exit sites and ER-to-Golgi trafficking of specific cargo, and did not require other autophagy proteins (e.g., ATG13). The defect in ER-to-Golgi trafficking activated the UPR pathway in ULK-deficient cells; both processes were reversed upon expression of SEC16A with a phosphomimetic substitution. Thus, the regulation of ER-to-Golgi trafficking by ULK1/2 is essential for cellular homeostasis.
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Joung Hyuck
authors.initials: JH
authors.lastname: Joo
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.|Integrated Biomedical Sciences Program, the University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin-Madison Medical School, Madison, WI, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Frankel
authors.affiliation: Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Ge
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Iyengar
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: XiuJie
authors.initials: X
authors.lastname: Li-Harms
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wright
authors.affiliation: St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN, USA.|Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Timothy I
authors.initials: TI
authors.lastname: Shaw
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN, USA.|Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Hendershot
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Fusun
authors.initials: F
authors.lastname: Kilic
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Ji Ying
authors.initials: JY
authors.lastname: Sze
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin-Madison Medical School, Madison, WI, USA.
authors.forename: Anjon
authors.initials: A
authors.lastname: Audhya
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
mesh_terms: D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7 / Q000235:genetics / Q000378:metabolism; D000071189:Autophagy-Related Protein-1 Homolog / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D022181:COP-Coated Vesicles / Q000201:enzymology; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D005838:Genotype; D006056:Golgi Apparatus / Q000201:enzymology* / Q000473:pathology; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D056811:Unfolded Protein Response; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D009687:Nuclear Proteins; C000611521:Sec13 protein, mouse; C000619639:Sec16a protein, mouse; C079038:Sec23a protein, mouse; D033921:Vesicular Transport Proteins; C512737:sec-23 protein, C elegans; C401061:Ulk2 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D000071193:Autophagy-Related Protein 7