1. The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis
- Author
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Rekha Iyengar, Mondira Kundu, Junmin Peng, Lu Xu, Fusun Kilic, Xiu Jie Li-Harms, Tullia Lindsten, Anjon Audhya, Linda M. Hendershot, Douglas R. Green, Ji Ying Sze, Christopher Wright, Bo Wang, Timothy I. Shaw, E.B. Frankel, Joung Hyuck Joo, and Liang Ge
- Subjects
Male ,0301 basic medicine ,Time Factors ,Cell ,Vesicular Transport Proteins ,Golgi Apparatus ,Cellular homeostasis ,Endoplasmic Reticulum ,Autophagy-Related Protein 7 ,0302 clinical medicine ,Ubiquitin ,Autophagy-Related Protein-1 Homolog ,Homeostasis ,Phosphorylation ,Mice, Knockout ,biology ,Brain ,Nuclear Proteins ,Autophagy-related protein 13 ,Cell biology ,Protein Transport ,Phenotype ,medicine.anatomical_structure ,symbols ,Female ,RNA Interference ,COP-Coated Vesicles ,Mice, 129 Strain ,Atg1 ,Genotype ,Protein Serine-Threonine Kinases ,Transfection ,symbols.namesake ,03 medical and health sciences ,Autophagy ,medicine ,Animals ,Humans ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Molecular Biology ,Endoplasmic reticulum ,Cell Biology ,Fibroblasts ,Golgi apparatus ,Mice, Inbred C57BL ,HEK293 Cells ,030104 developmental biology ,Nerve Degeneration ,Unfolded Protein Response ,Unfolded protein response ,biology.protein ,Carrier Proteins ,030217 neurology & neurosurgery - 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.
- Published
- 2016
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