title: ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization.
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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: David Tse Shen
authors.identifier: http://orcid.org/0000-0001-5695-9446
authors.initials: DT
authors.lastname: Lin
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Conibear
mesh_terms: D000818:Animals; D002460:Cell Line; D000076122:Disks Large Homolog 4 Protein; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010168:Palmitates; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: ABHD17A; ABHD17B; ABHD17C; APT1; Acyl Protein Thioesterase; FAM108A1; FAM108B1; FAM108C1; N-Ras; PSD95; Palmostatin B; biochemistry; cell biology; depalmitoylation; human; palmitoylation