NIPSNAP1 and NIPSNAP2 act as "eat me" signals to allow sustained recruitment of autophagy receptors during mitophagy

Autophagy. 2019 Oct;15(10):1845-1847. doi: 10.1080/15548627.2019.1637642. Epub 2019 Jul 4.

Abstract

Removal of damaged mitochondria is vital for cellular homeostasis especially in non-dividing cells, like neurons. Damaged mitochondria that cannot be repaired by the ubiquitin-proteasomal system are cleared by a form of selective autophagy known as mitophagy. Following damage, mitochondria become labelled with 'eat-me' signals that selectively determine their degradation. Recently, we identified the mitochondrial matrix proteins, NIPSNAP1 (nipsnap homolog 1) and NIPSNAP2 as 'eat-me' signals for damaged mitochondria. NIPSNAP1 and NIPSNAP2 accumulate on the mitochondrial outer membrane following mitochondrial depolarization, recruiting autophagy receptors and adaptors, as well as human Atg8 (autophagy-related 8)-family proteins to facilitate mitophagy. The NIPSNAPs allow a sustained recruitment of SQSTM1-like receptors (SLRs) to ensure efficient mitophagy. Zebrafish lacking Nipsnap1 show decreased mitophagy in the brain coupled with increased ROS production, loss of dopaminergic neurons and strongly reduced locomotion.

Keywords: Atg8; NIPSNAP1; NIPSNAP2; PINK1/Parkin; SLRs; mitophagy; ‘eat me’ signal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Autophagy
  • Autophagy-Related Protein 8 Family / genetics
  • Autophagy-Related Protein 8 Family / metabolism
  • Autophagy-Related Proteins / metabolism*
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Membrane Proteins / physiology*
  • Mitophagy / genetics*
  • Protein Binding
  • Sequestosome-1 Protein / chemistry
  • Sequestosome-1 Protein / metabolism
  • Signal Transduction / genetics
  • Zebrafish

Substances

  • Autophagy-Related Protein 8 Family
  • Autophagy-Related Proteins
  • GABARAPL2 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NIPSNAP1 protein, human
  • NIPSNAP2 protein, human
  • Sequestosome-1 Protein

Grant support

This work was funded by the TOPPFORSK program (grant numbers 249884 to TJ and 221831 to AS) and the Centres of Excellence funding scheme (project number 262652) of the Research Council of Norway as well as the Norwegian Cancer Society (grant numbers 190214 to TJ and 171318 to AS); Kreftforeningen [190214]; Kreftforeningen [171318]; Norges Forskningsråd [221831]; Norges Forskningsråd [249884]; Norges Forskningsråd [262652].