@article{0f3ffa4153ce45858d921fa56f14306d,
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. Joo et al. demonstrate that the autophagy-inducing kinases ULK1 and ULK2 regulate ER-to-Golgi trafficking of specific cargo by phosphorylating the COPII scaffold SEC16A. This non-canonical (ATG13-independent) function of the ULKs is essential for maintaining cellular homeostasis under basal physiologic conditions.",
author = "Joo, {Joung Hyuck} and Bo Wang and Elisa Frankel and Liang Ge and Lu Xu and Rekha Iyengar and Li-Harms, {Xiu Jie} and Christopher Wright and Shaw, {Timothy I.} and Tullia Lindsten and Green, {Douglas R.} and Junmin Peng and Hendershot, {Linda M.} and Fusun Kilic and Sze, {Ji Ying} and Anjon Audhya and Mondira Kundu",
note = "Funding Information: We are grateful to Terrence Geiger (St. Jude Children{\textquoteright}s Research Hospital [St. Jude]), Toshifumi Tomoda (Beckman Research Institute of City of Hope), Masaaki Komatsu (Tokyo Metropolitan Institute of Medical Science), and Do-Hyung Kim (University of Minnesota) for reagents. We are grateful to Angela McArthur and Keith Laycock (St. Jude) for editing the manuscript. The mass spectrometry analysis was performed by staff in the St. Jude Proteomics Facility. Histological analyses were performed by Peter Vogel in the St. Jude Veterinary Pathology Core, and most of the imaging data were acquired in the St. Jude Cell and Tissue Imaging Center. The St. Jude core facility resources are supported by Cancer Center Support Grant P30 CA021765 from the National Cancer Institute and by ALSAC. The research was partially supported by grants from the National Heart, Lung, and Blood Institute (R01 HL114697 to M.K. and R01 HL091196 to F.K.), the National Institute of Child Health and Human Development (R01 HD058697 and R01 HD053477 to F.K.), the National Institute of General Medical Sciences (R01 GM110567 to A.A. and K99 GM114397 to L.G.), the National Institute of Ageing (AG047928 to J. P.), the National Institute of Mental Health (MH105389 to J.S.), the Burroughs Welcome Fund (1006062.05 to M.K.), the American Society of Hematology (to M.K.), the American Heart Association (GRNT17240014 to F.K.), and ALSAC (to M.K., J.P, D.R.G., and L.H.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = may,
day = "19",
doi = "10.1016/j.molcel.2016.04.020",
language = "English (US)",
volume = "62",
pages = "491--506",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}