TRIM37 deficiency induces autophagy through deregulating the MTORC1-TFEB axis

Autophagy. 2018;14(9):1574-1585. doi: 10.1080/15548627.2018.1463120. Epub 2018 Aug 21.

Abstract

TRIM37 gene mutations cause mulibrey (muscle-liver-brain-eye) nanism, a severe growth disorder with prenatal onset. Although TRIM37 depletion normally induces apoptosis, patients with TRIM37 mutations have a high risk of developing tumors, suggesting that there may be an alternative pro-survival mechanism for TRIM37-deficient tumor cells. We find that TRIM37 interacts with MTOR and RRAGB proteins, enhances the MTOR-RRAGB interaction and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. In response to loss of TRIM37 functions, phosphorylation of TFEB is significantly reduced, resulting in its translocation into the nucleus enabling its transcriptional activation of genes involved in lysosome biogenesis and macroautophagy/autophagy. The enhanced autophagy depends on the inhibition of MTORC1 signaling and may serve as an alternative mechanism to survive the loss of TRIM37 functions. Our study unveils a positive role of TRIM37 in regulating the MTORC1-TFEB axis and provides mechanistic insights into the pathogenesis of mulibrey nanism, as well as potential therapeutic treatment.

Abbreviations: ACTB: actin beta; ATG: autophagy related; CASP3: caspase3; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; CTS: cathepsin proteases; CTSL: cathepsin L; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LMNB1: lamin B1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; mulibrey: muscle-liver-brain-eye; NAC: N-acetyl-L-cysteine; PARP1: poly(ADP-ribose) polymerase 1; RAP2A: member of RAS oncogene family; RHEB: Ras homolog enriched in brain; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; RRAGB: Ras related GTP binding B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TRIM37: tripartite motif containing 37.

Keywords: Autophagy; MTORC1; TFEB; TRIM37; lysosome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids / pharmacology
  • Autophagy*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Monomeric GTP-Binding Proteins / metabolism
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Signal Transduction* / drug effects
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases

Substances

  • Amino Acids
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Nuclear Proteins
  • TFEB protein, human
  • Tripartite Motif Proteins
  • TRIM37 protein, human
  • Ubiquitin-Protein Ligases
  • Mechanistic Target of Rapamycin Complex 1
  • RRAGB protein, human
  • Monomeric GTP-Binding Proteins