ABHD17 Proteins Are Novel Protein Depalmitoylases That Regulate N-Ras Palmitate Turnover and Subcellular Localization

Elife. 2015 Dec 23;4:e11306. doi: 10.7554/eLife.11306.

Abstract

Dynamic changes in protein S-palmitoylation are critical for regulating protein localization and signaling. Only two enzymes - the acyl-protein thioesterases APT1 and APT2 - are known to catalyze palmitate removal from cytosolic cysteine residues. It is unclear if these enzymes act constitutively on all palmitoylated proteins, or if additional depalmitoylases exist. Using a dual pulse-chase strategy comparing palmitate and protein half-lives, we found knockdown or inhibition of APT1 and APT2 blocked depalmitoylation of Huntingtin, but did not affect palmitate turnover on postsynaptic density protein 95 (PSD95) or N-Ras. We used activity profiling to identify novel serine hydrolase targets of the APT1/2 inhibitor Palmostatin B, and discovered that a family of uncharacterized ABHD17 proteins can accelerate palmitate turnover on PSD95 and N-Ras. ABHD17 catalytic activity is required for N-Ras depalmitoylation and re-localization to internal cellular membranes. Our findings indicate that the family of depalmitoylation enzymes may be substantially broader than previously believed.

Keywords: ABHD17A; ABHD17B; ABHD17C; APT1; Acyl Protein Thioesterase; FAM108A1; FAM108B1; FAM108C1; N-Ras; PSD95; Palmostatin B; biochemistry; cell biology; depalmitoylation; human; palmitoylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disks Large Homolog 4 Protein
  • GTP Phosphohydrolases / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Intracellular Membranes / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism*
  • Palmitates / metabolism*
  • Protein Processing, Post-Translational*
  • Protein Transport

Substances

  • DLG4 protein, human
  • Disks Large Homolog 4 Protein
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Palmitates
  • GTP Phosphohydrolases
  • NRAS protein, human