Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade

Elife. 2017 Aug 15:6:e27826. doi: 10.7554/eLife.27826.


S-Palmitoylation is the only reversible post-translational lipid modification. Knowledge about the DHHC palmitoyltransferase family is still limited. Here we show that human ZDHHC6, which modifies key proteins of the endoplasmic reticulum, is controlled by an upstream palmitoyltransferase, ZDHHC16, revealing the first palmitoylation cascade. The combination of site specific mutagenesis of the three ZDHHC6 palmitoylation sites, experimental determination of kinetic parameters and data-driven mathematical modelling allowed us to obtain detailed information on the eight differentially palmitoylated ZDHHC6 species. We found that species rapidly interconvert through the action of ZDHHC16 and the Acyl Protein Thioesterase APT2, that each species varies in terms of turnover rate and activity, altogether allowing the cell to robustly tune its ZDHHC6 activity.

Keywords: Acyl protein thioesterase; DHHC; ERAD; cell biology; endoplasmic reticulum; human; mouse; palmitoylation; turnover.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / chemistry
  • Acyltransferases / metabolism*
  • Cysteine / metabolism
  • Endoplasmic Reticulum-Associated Degradation
  • HeLa Cells
  • Humans
  • Lipoylation*
  • Models, Biological
  • Protein Transport
  • Proteolysis
  • Thiolester Hydrolases / metabolism
  • src Homology Domains


  • ZDHHC6 protein, human
  • Acyltransferases
  • ZDHHC16 protein, human
  • LYPLA2 protein, human
  • Thiolester Hydrolases
  • Cysteine

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.