한빛사논문
- 조회2,000
Abstract
Joung Hyuck Joo,1,13 Bo Wang,1,2,13 Elisa Frankel,3 Liang Ge,4 Lu Xu,5 Rekha Iyengar,1 XiuJie Li-Harms,1 Christopher Wright,1 Timothy I. Shaw,6,7 Tullia Lindsten,8 Douglas R. Green,9 Junmin Peng,6,10 Linda M. Hendershot,11 Fusun Kilic,12 Ji Ying Sze,5 Anjon Audhya,3 and Mondira Kundu1,*
1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
2Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA
3Department of Biomolecular Chemistry, University of Wisconsin, Madison Medical School, Madison, WI 53706, USA
4Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, CA 94720, USA
5Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
6St. Jude Proteomics Facility, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
7Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
8Immunology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA
9Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
10Departments of Structural Biology and Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
11Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
12Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
13Co-first author
*Correspondence : Mondira Kundu
Summary
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.
논문정보
- Research article
- 2016년 05월 (BRIC 등록일 2016-05-25)
- 국외 연구진
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