Site-specific deacylation by ABHD17a controls BK channel splice variant activity

Abstract

S-acylation, the reversible post-translational lipid modification of proteins is an important mechanism to control the properties and function of ion channels and other polytopic transmembrane proteins. However, while increasing evidence reveals the role of diverse acyl protein transferases (zDHHC) in controlling ion channel S-acylation the acyl protein thioesterases that control ion channel deacylation are very poorly defined. Here we show that the α/β-hydrolase domain-containing protein 17a (ABHD17a) deacylates the STREX domain of large conductance voltage- and calcium- activated potassium (BK) channels inhibiting channel activity independently of effects on channel surface expression. Importantly, ABHD17a deacylates BK channels in a site- specific manner as it has no effect on the S-acylated S0-S1 domain conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases revealing mechanisms for generating both specificity and diversity for these important enzymes to control the properties and functions of ion channels.

Identification of biomarkers for immunotherapy response in prostate cancer and potential drugs to alleviate immunosuppression

“…ABHD17A (α/β-hydrolase domain-containing protein 17a) is another biomarker related to voltage channels. Previous research demonstrated that ABHD17A modulates ion channels at the post-transcriptional level by deacetylating the stressregulated exon domains of large conductance voltageand calcium-activated potassium channels [14]. Moreover, low expression of ABHD17A is associated with improved overall survival of PRCA according to survival analysis.…”

Substrate recruitment by zDHHC protein acyltransferases

“…Interestingly, the STREX variant of the BK channel includes a CTD that is palmitoylated and modified by a distinct set of zDHHC proteins [ 90 ]. Adding to this complexity is the reversibility of palmitoylation at both the first intracellular loop and the C-terminal STREX domain, where depalmitoylation is mediated by distinct acylprotein thioesterases [ 89 , 91 ].…”

Regulatory effects of protein S-acylation on insulin secretion and insulin action

“…Indeed, genetic knockdown of zDHHC23, or site-directed mutagenesis of Cys53 : 56 to alanine results in reduced cell surface expression and enhanced retention of the α-subunit in the endoplasmic reticulum [ 53 – 55 ]. The S0–S1 site is de-acylated by the thioesterases APT1 (Lypla1) and the related APT1-like thioesterase (Lyplal1) resulting in enhanced retention in the trans Golgi network [ 55 , 56 ]. Lyplal1 has been associated with type 2 diabetes [ 57 ] including through use of first-phase insulin secretion as a marker to identify candidate interacting SNPs [ 58 ].…”

“…An siRNA-based screen revealed the STREX insert is S-acylated by multiple zDHHCs including the plasma membrane localized zDHHC5 and Golgi located zDHHC17, with zDHHC17 being the major zDHHC controlling the STREX domain in HEK293 cells [ 63 , 64 ]. Conversely, STREX is almost exclusively de-acylated by the plasma membrane localized thioesterase ABHD17a (also by ABHD17c but not the related ABHD17b) [ 56 ]. Thus, STREX is S-acylated and de-acylated by distinct enzymes compared to those that control S-acylation of the conserved S0–S1 domain.…”