TY - JOUR
T1 - Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression
AU - Liu, Zhengzhao
AU - Chen, Peng
AU - Gao, Hong
AU - Gu, Yu
AU - Yang, Jiao
AU - Peng, Hong
AU - Xu, Xingxing
AU - Wang, Haifeng
AU - Yang, Meiqiang
AU - Liu, Xiaoying
AU - Fan, Libin
AU - Chen, Shiyao
AU - Zhou, Jian
AU - Sun, Yihong
AU - Ruan, Kangchen
AU - Cheng, Shuqun
AU - Komatsu, Masaaki
AU - White, Eileen
AU - Li, Lin
AU - Ji, Hongbin
AU - Finley, Daniel
AU - Hu, Ronggui
N1 - Funding Information:
The authors are thankful to Drs. Qingrun Li and Rong Zeng for assistance in the mass spectra analysis. We also acknowledge the excellent support from the animal facility and the imaging center of SIBCB. We thank Dr. Yalan Wu and all other members of the Hu lab for their support. This work was supported by funding from the National Science Foundation of China to R.H. (31270828 and 31070678) and grants from the Ministry of Science and Technology, China (2012CB910800 and 2013CB910900 to R.H., 2010CB912101 to H.J. and L.L., and 2011CB915501 to K.R.), and by NIH grant GM095526 (to D.F.). R.H. was also supported by a Sanofi-aventis SIBS Young Investigator award and funding from the Cancer Center of Xuhui Central Hospital (CCR2012003), Shanghai Institute of Neurosciences (SKLN-201206), and the Instrument Developing Project of the Chinese Academy of Sciences (YZ201339). We are particularly grateful to Dr. Ivan Dikic (Goethe University, Germany) for advice on experimental design and to Drs. Dangsheng Li and Lijian Hui of SIBCB, Dan Wu of Yale University, and Zhenggang Liu of the National Cancer Institute USA for helpful discussions.
PY - 2014/7/14
Y1 - 2014/7/14
N2 - In selective autophagy, receptors are central for cargo selection and delivery. However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy. Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor. Here we report that tumor-suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, the Lys48-linked polyubiquitin chains that HACE1 conjugates onto OPTN might predominantly target OPTN for autophagic degradation. By demonstrating that the HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, our findings may open an avenue for developing autophagy-targeted therapeutic intervention into cancer.
AB - In selective autophagy, receptors are central for cargo selection and delivery. However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy. Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor. Here we report that tumor-suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, the Lys48-linked polyubiquitin chains that HACE1 conjugates onto OPTN might predominantly target OPTN for autophagic degradation. By demonstrating that the HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, our findings may open an avenue for developing autophagy-targeted therapeutic intervention into cancer.
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U2 - 10.1016/j.ccr.2014.05.015
DO - 10.1016/j.ccr.2014.05.015
M3 - Article
C2 - 25026213
AN - SCOPUS:84904256742
SN - 1535-6108
VL - 26
SP - 106
EP - 120
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -