CERKL regulates autophagy via the NAD-dependent deacetylase SIRT1

Xuebin Hu; Zhaojing Lu; Shanshan Yu; James Reilly; Fei Liu; Danna Jia; Yayun Qin; Shanshan Han; Xiliang Liu; Zhen Qu; Yuexia Lv; Jingzhen Li; Yuwen Huang; Tao Jiang; Haibo Jia; Qing Wang; Jingyu Liu; Xinhua Shu; Zhaohui Tang; Mugen Liu

doi:10.1080/15548627.2018.1520548

CERKL regulates autophagy via the NAD-dependent deacetylase SIRT1

Autophagy. 2019 Mar;15(3):453-465. doi: 10.1080/15548627.2018.1520548. Epub 2018 Sep 25.

Authors

Xuebin Hu¹, Zhaojing Lu¹, Shanshan Yu¹, James Reilly², Fei Liu¹, Danna Jia¹, Yayun Qin¹, Shanshan Han, Xiliang Liu¹, Zhen Qu¹, Yuexia Lv¹, Jingzhen Li¹, Yuwen Huang¹, Tao Jiang¹, Haibo Jia¹, Qing Wang¹, Jingyu Liu¹, Xinhua Shu², Zhaohui Tang¹, Mugen Liu¹

Affiliations

¹ a Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology , College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan , Hubei , P.R. China.
² b Department of Life Sciences , Glasgow Caledonian University , Glasgow , UK.

Abstract

Macroautophagy/autophagy is an important intracellular mechanism for the maintenance of cellular homeostasis. Here we show that the CERKL (ceramide kinase like) gene, a retinal degeneration (RD) pathogenic gene, plays a critical role in regulating autophagy by stabilizing SIRT1. In vitro and in vivo, suppressing CERKL results in impaired autophagy. SIRT1 is one of the main regulators of acetylation/deacetylation in autophagy. In CERKL-depleted retinas and cells, SIRT1 is downregulated. ATG5 and ATG7, 2 essential components of autophagy, show a higher degree of acetylation in CERKL-depleted cells. Overexpression of SIRT1 rescues autophagy in CERKL-depleted cells, whereas CERKL loses its function of regulating autophagy in SIRT1-depleted cells, and overexpression of CERKL upregulates SIRT1. Finally, we show that CERKL directly interacts with SIRT1, and may regulate its phosphorylation at Ser27 to stabilize SIRT1. These results show that CERKL is an important regulator of autophagy and it plays this role by stabilizing the deacetylase SIRT1.

Keywords: Autophagy; CERKL; SIRT1; deacetylation; retinitis pigmentosa; stabilization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Autophagosomes / metabolism
Autophagy / genetics*
Autophagy-Related Protein 5 / chemistry
Autophagy-Related Protein 5 / genetics
Autophagy-Related Protein 5 / metabolism
Autophagy-Related Protein 7 / chemistry
Autophagy-Related Protein 7 / genetics
Autophagy-Related Protein 7 / metabolism
Cell Line
Disease Models, Animal
Humans
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) / genetics*
Phosphotransferases (Alcohol Group Acceptor) / metabolism*
Protein Processing, Post-Translational / genetics
Retina / pathology
Retinal Degeneration / genetics*
Retinal Pigment Epithelium / metabolism
Retinitis Pigmentosa / genetics
Sirtuin 1 / chemistry
Sirtuin 1 / genetics
Sirtuin 1 / metabolism*
Up-Regulation
Zebrafish / genetics
Zebrafish / metabolism
Zebrafish Proteins / genetics*
Zebrafish Proteins / metabolism

Substances

ATG5 protein, human
Autophagy-Related Protein 5
Zebrafish Proteins
Phosphotransferases (Alcohol Group Acceptor)
Cerkl protein, zebrafish
ceramide kinase
SIRT1 protein, human
Sirtuin 1
ATG7 protein, human
Autophagy-Related Protein 7

Grants and funding

National Natural Science Foundation of China (No. 81870691, 31471194, 81371064, 81500762, 81670890, 81800870 and 31801041).