SNAP23 regulates BAX-dependent adipocyte programmed cell death independently of canonical macroautophagy

J Clin Invest. 2018 Aug 31;128(9):3941-3956. doi: 10.1172/JCI99217. Epub 2018 Aug 13.


The t-SNARE protein SNAP23 conventionally functions as a component of the cellular machinery required for intracellular transport vesicle fusion with target membranes and has been implicated in the regulation of fasting glucose levels, BMI, and type 2 diabetes. Surprisingly, we observed that adipocyte-specific KO of SNAP23 in mice resulted in a temporal development of severe generalized lipodystrophy associated with adipose tissue inflammation, insulin resistance, hyperglycemia, liver steatosis, and early death. This resulted from adipocyte cell death associated with an inhibition of macroautophagy and lysosomal degradation of the proapoptotic regulator BAX, with increased BAX activation. BAX colocalized with LC3-positive autophagic vacuoles and was increased upon treatment with lysosome inhibitors. Moreover, BAX deficiency suppressed the lipodystrophic phenotype in the adipocyte-specific SNAP23-KO mice and prevented cell death. In addition, ATG9 deficiency phenocopied SNAP23 deficiency, whereas ATG7 deficiency had no effect on BAX protein levels, BAX activation, or apoptotic cell death. These data demonstrate a role for SNAP23 in the control of macroautophagy and programmed cell death through an ATG9-dependent, but ATG7-independent, pathway regulating BAX protein levels and BAX activation.

Keywords: Adipose tissue; Apoptosis; Autophagy; Cell Biology; Metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / metabolism*
  • Animals
  • Apoptosis / physiology
  • Autophagy / physiology
  • Autophagy-Related Protein 7 / deficiency
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism
  • Autophagy-Related Proteins / deficiency
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Lipodystrophy / metabolism
  • Lipodystrophy / pathology
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Proteolysis
  • Qb-SNARE Proteins / deficiency
  • Qb-SNARE Proteins / genetics
  • Qb-SNARE Proteins / metabolism*
  • Qc-SNARE Proteins / deficiency
  • Qc-SNARE Proteins / genetics
  • Qc-SNARE Proteins / metabolism*
  • Vesicular Transport Proteins / deficiency
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism
  • bcl-2-Associated X Protein / deficiency
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*


  • Atg7 protein, mouse
  • Atg9A protein, mouse
  • Autophagy-Related Proteins
  • Bax protein, mouse
  • Membrane Proteins
  • Qb-SNARE Proteins
  • Qc-SNARE Proteins
  • Snap23 protein, mouse
  • Vesicular Transport Proteins
  • bcl-2-Associated X Protein
  • Autophagy-Related Protein 7