G-protein Coupled Receptors Regulate Autophagy by ZBTB16-mediated Ubiquitination and Proteasomal Degradation of Adaptor Protein Atg14L

Tao Zhang; Kangyun Dong; Wei Liang; Daichao Xu; Hongguang Xia; Jiefei Geng; Ayaz Najafov; Min Liu; Yanxia Li; Xiaoran Han; Juan Xiao; Zhenzhen Jin; Ting Peng; Yang Gao; Yu Cai; Chunting Qi; Qing Zhang; Anyang Sun; Marta Lipinski; Hong Zhu; Yue Xiong; Pier Paolo Pandolfi; He Li; Qiang Yu; Junying Yuan

doi:10.7554/eLife.06734

G-protein Coupled Receptors Regulate Autophagy by ZBTB16-mediated Ubiquitination and Proteasomal Degradation of Adaptor Protein Atg14L

Tao Zhang, Kangyun Dong, Wei Liang, Daichao Xu, Hongguang Xia, Jiefei Geng, Ayaz Najafov, Min Liu, Yanxia Li, Xiaoran Han, Juan Xiao, Zhenzhen Jin, Ting Peng, Yang Gao, Yu Cai, Chunting Qi, Qing Zhang, Anyang Sun, Marta Lipinski, Hong ZhuYue Xiong, Pier Paolo Pandolfi, He Li, Qiang Yu, Junying Yuan

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

Abstract

Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian orthologue of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. Here we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of GPCR ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington’s disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.

Original language	English (US)
Article number	e06734
Journal	eLife
Volume	2015
Issue number	4
DOIs	https://doi.org/10.7554/eLife.06734
State	Published - Mar 30 2015
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.7554/eLife.06734

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Zhang, T., Dong, K., Liang, W., Xu, D., Xia, H., Geng, J., Najafov, A., Liu, M., Li, Y., Han, X., Xiao, J., Jin, Z., Peng, T., Gao, Y., Cai, Y., Qi, C., Zhang, Q., Sun, A., Lipinski, M., ... Yuan, J. (2015). G-protein Coupled Receptors Regulate Autophagy by ZBTB16-mediated Ubiquitination and Proteasomal Degradation of Adaptor Protein Atg14L. eLife, 2015(4), Article e06734. https://doi.org/10.7554/eLife.06734

Zhang, T, Dong, K, Liang, W, Xu, D, Xia, H, Geng, J, Najafov, A, Liu, M, Li, Y, Han, X, Xiao, J, Jin, Z, Peng, T, Gao, Y, Cai, Y, Qi, C, Zhang, Q, Sun, A, Lipinski, M, Zhu, H, Xiong, Y, Pandolfi, PP, Li, H, Yu, Q & Yuan, J 2015, 'G-protein Coupled Receptors Regulate Autophagy by ZBTB16-mediated Ubiquitination and Proteasomal Degradation of Adaptor Protein Atg14L', eLife, vol. 2015, no. 4, e06734. https://doi.org/10.7554/eLife.06734

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title = "G-protein Coupled Receptors Regulate Autophagy by ZBTB16-mediated Ubiquitination and Proteasomal Degradation of Adaptor Protein Atg14L",

abstract = "Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian orthologue of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. Here we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of GPCR ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington{\textquoteright}s disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.",

author = "Tao Zhang and Kangyun Dong and Wei Liang and Daichao Xu and Hongguang Xia and Jiefei Geng and Ayaz Najafov and Min Liu and Yanxia Li and Xiaoran Han and Juan Xiao and Zhenzhen Jin and Ting Peng and Yang Gao and Yu Cai and Chunting Qi and Qing Zhang and Anyang Sun and Marta Lipinski and Hong Zhu and Yue Xiong and Pandolfi, {Pier Paolo} and He Li and Qiang Yu and Junying Yuan",

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AU - Zhang, Tao

AU - Dong, Kangyun

AU - Liang, Wei

AU - Xu, Daichao

AU - Xia, Hongguang

AU - Geng, Jiefei

AU - Najafov, Ayaz

AU - Liu, Min

AU - Li, Yanxia

AU - Han, Xiaoran

AU - Xiao, Juan

AU - Jin, Zhenzhen

AU - Peng, Ting

AU - Gao, Yang

AU - Cai, Yu

AU - Qi, Chunting

AU - Zhang, Qing

AU - Sun, Anyang

AU - Lipinski, Marta

AU - Zhu, Hong

AU - Xiong, Yue

AU - Pandolfi, Pier Paolo

AU - Li, He

AU - Yu, Qiang

AU - Yuan, Junying

PY - 2015/3/30

Y1 - 2015/3/30

N2 - Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian orthologue of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. Here we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of GPCR ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington’s disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.

AB - Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian orthologue of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. Here we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of GPCR ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington’s disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.

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G-protein Coupled Receptors Regulate Autophagy by ZBTB16-mediated Ubiquitination and Proteasomal Degradation of Adaptor Protein Atg14L

Abstract

ASJC Scopus subject areas

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