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Mol Cell. 2016 May 19;62(4):491-506. doi: 10.1016/j.molcel.2016.04.020.

The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis.

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
2
Integrated Biomedical Sciences Program, the University of Tennessee Health Science Center, Memphis, TN, USA.
3
Department of Biomolecular Chemistry, University of Wisconsin-Madison Medical School, Madison, WI, USA.
4
Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA, USA.
5
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
6
St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN, USA.
7
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
8
Immunology Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
9
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
10
Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
11
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
12
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
#
Contributed equally

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.

PMID:
27203176
PMCID:
PMC4993601
DOI:
10.1016/j.molcel.2016.04.020
[Indexed for MEDLINE]
Free PMC Article

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