Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy

Autophagy. 2015;11(8):1216-29. doi: 10.1080/15548627.2015.1017180.

Abstract

Mitochondria serve as membrane sources and signaling platforms for regulating autophagy. Accumulating evidence has also shown that damaged mitochondria are removed through both selective mitophagy and general autophagy in response to mitochondrial and oxidative stresses. Protein ubiquitination through mitochondrial E3 ligases plays an integrative role in mitochondrial outer membrane protein degradation, mitochondrial dynamics, and mitophagy. Here we showed that MUL1, a mitochondria-localized E3 ligase, regulates selenite-induced mitophagy in an ATG5 and ULK1-dependent manner. ULK1 partially translocated to mitochondria after selenite treatment and interacted with MUL1. We also demonstrated that ULK1 is a novel substrate of MUL1. These results suggest the association of mitochondria with autophagy regulation and provide a new mechanism for the beneficial effects of selenium as a chemopreventive agent.

Keywords: E3 ligase; MUL1; ULK1; mitophagy; selenite.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autophagy*
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein-1 Homolog
  • Gene Expression Regulation, Enzymologic
  • Glutathione Transferase / metabolism
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / pathology
  • Mitochondrial Proteins / metabolism*
  • Mitophagy*
  • Molecular Sequence Data
  • Oxidative Stress
  • Protein-Serine-Threonine Kinases / chemistry*
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / chemistry
  • Selenious Acid / chemistry*
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • ATG5 protein, human
  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Green Fluorescent Proteins
  • MUL1 protein, human
  • MUL1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Glutathione Transferase
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human
  • Ulk1 protein, mouse
  • Selenious Acid