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

Joung Hyuck Joo, Bo Wang, Elisa Frankel, Liang Ge, Lu Xu, Rekha Iyengar, Xiu Jie Li-Harms, Christopher Wright, Timothy I. Shaw, Tullia Lindsten, Douglas R. Green, Junmin Peng, Linda M. Hendershot, Fusun Kilic, Ji Ying Sze, Anjon Audhya, Mondira Kundu

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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.

Original languageEnglish (US)
Pages (from-to)491-506
Number of pages16
JournalMolecular Cell
Volume62
Issue number4
DOIs
StatePublished - May 19 2016

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Autophagy
Endoplasmic Reticulum
Homeostasis
Unfolded Protein Response
Nerve Degeneration
Ubiquitin
Proteomics
Phosphotransferases
Phosphorylation
Brain
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Joo, J. H., Wang, B., Frankel, E., Ge, L., Xu, L., Iyengar, R., ... Kundu, M. (2016). The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis. Molecular Cell, 62(4), 491-506. https://doi.org/10.1016/j.molcel.2016.04.020

The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis. / Joo, Joung Hyuck; Wang, Bo; Frankel, Elisa; Ge, Liang; Xu, Lu; Iyengar, Rekha; Li-Harms, Xiu Jie; Wright, Christopher; Shaw, Timothy I.; Lindsten, Tullia; Green, Douglas R.; Peng, Junmin; Hendershot, Linda M.; Kilic, Fusun; Sze, Ji Ying; Audhya, Anjon; Kundu, Mondira.

In: Molecular Cell, Vol. 62, No. 4, 19.05.2016, p. 491-506.

Research output: Contribution to journalArticle

Joo, JH, Wang, B, Frankel, E, Ge, L, Xu, L, Iyengar, R, Li-Harms, XJ, Wright, C, Shaw, TI, Lindsten, T, Green, DR, Peng, J, Hendershot, LM, Kilic, F, Sze, JY, Audhya, A & Kundu, M 2016, 'The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis', Molecular Cell, vol. 62, no. 4, pp. 491-506. https://doi.org/10.1016/j.molcel.2016.04.020
Joo, Joung Hyuck ; Wang, Bo ; Frankel, Elisa ; Ge, Liang ; Xu, Lu ; Iyengar, Rekha ; Li-Harms, Xiu Jie ; Wright, Christopher ; Shaw, Timothy I. ; Lindsten, Tullia ; Green, Douglas R. ; Peng, Junmin ; Hendershot, Linda M. ; Kilic, Fusun ; Sze, Ji Ying ; Audhya, Anjon ; Kundu, Mondira. / The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis. In: Molecular Cell. 2016 ; Vol. 62, No. 4. pp. 491-506.
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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.",
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AU - Peng, Junmin

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