Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression

Cancer Cell. 2014 Jul 14;26(1):106-20. doi: 10.1016/j.ccr.2014.05.015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Autophagy*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Damage
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • HEK293 Cells
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Lysine
  • Macrophages / enzymology
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Oxidative Stress
  • Protein Binding
  • RNA Interference
  • Sequestosome-1 Protein
  • Signal Transduction
  • Time Factors
  • Transcription Factor TFIIIA / genetics
  • Transcription Factor TFIIIA / metabolism*
  • Transfection
  • Tumor Burden
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Eye Proteins
  • Heat-Shock Proteins
  • MAP1LC3A protein, human
  • Membrane Transport Proteins
  • Microtubule-Associated Proteins
  • OPTN protein, human
  • Optn protein, mouse
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Transcription Factor TFIIIA
  • Tumor Suppressor Proteins
  • HACE1 protein, human
  • HACE1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Lysine