Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression

Jul 23, 2014     Email"> PrintText Size

Autophagy is an evolutionarily conserved process that delivers unnecessary, damaged or dysfunctional components to lysosome for degradation. Autophagy, once believed to be non-selective, can selectively target cargos for lysosome-dependent degradation. In the cell, such selectivity is achieved by a family of approximately ten proteins, namely autophagy receptors, which specifically recognize the cargos and target them for autophagic degradation. Mutations in the genes of different autophagy receptors, which could impact on the cellular autophagy activity to varying extents, might mechanistically underlie distinct human disorders including cancer. 

For example, Optimeurin (OPTN), whose gene mutations are associated with Primary Open Angle Glaucoma, Amyotrophic Lateral Sclerosis (ALS) or Paget’s bone disease, was recently identified as a new member of the autophagy receptor family. It remains unclear whether and how these autophagy receptors might form a physical complex and function concertedly in controlling autophagy. 

Dr. HU Ronggui’s group at the Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences first discovered that a tumor suppressing E3 ubiquitin ligase, HACE1, interacts with and ubiquitylates OPTN. HACE1-ubiquitylated OPTN could subsequently interact with the UBA domain of p62 to form a larger autophagy receptor complex and accelerate cellular autophagic flux.  

This work has thus revealed a previously unappreciated mode of delicate regulations on selective autophagy by ubiquitin signaling. There were also data indicated that HACE1 and OPTN are frequently mutated or down-regulated in multiple human cancers and restoring the function of HACE1-OPTN axis could activate autophagy and suppress tumor.  

Taken together, these findings might have thus opened a new avenue to develop autophagy-targeted therapeutic intervention into cancer. 

This work was published in the latest issue of Cancer Cell under the title “Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression” on July 14, 2014. Under the supervision by Dr. HU Ronggui, the study was led by co-first authors: Ph.D candidates LIU Zhengzhao, CHEN Peng from Dr. HU Ronggui’s group at SIBCB, and Dr. GAO Hong from Fudan Medical School. The major collaborators included Drs. JI Hongbing, RUAN Kangcheng, LI Lin from SIBCB as well as Dr. Daniel Finley from Harvard Medical School.  

This work was supported by the National Science Foundation of China, the Ministry of Science and Technology, China, Sanofi-aventis SIBS Young Investigator award and funding from the Cancer Center of Xuhui Central Hospital, Shanghai Institute of Neurosciences, PuJiang Talents award and the 100 Talents Program of the Chinese Academy of Sciences. 

  

A schematic view of how the HACE1-OPTN axis might activate selective autophagy and suppress tumor (Image by Prof HU Ronggui`s group)