Depalmitoylation by Palmitoyl-Protein Thioesterase 1 in Neuronal Health and Degeneration

Abstract

Protein palmitoylation is the post-translational, reversible addition of a 16-carbon fatty acid, palmitate, to proteins. Protein palmitoylation has recently garnered much attention, as it robustly modifies the localization and function of canonical signaling molecules and receptors. Protein depalmitoylation, on the other hand, is the process by which palmitic acid is removed from modified proteins and contributes, therefore, comparably to palmitoylated-protein dynamics. Palmitoylated proteins also require depalmitoylation prior to lysosomal degradation, demonstrating the significance of this process in protein sorting and turnover. Palmitoylation and depalmitoylation serve as particularly crucial regulators of protein function in neurons, where a specialized molecular architecture and cholesterol-rich membrane microdomains contribute to synaptic transmission. Three classes of depalmitoylating enzymes are currently recognized, the acyl protein thioesterases, α/β hydrolase domain-containing 17 proteins (ABHD17s), and the palmitoyl-protein thioesterases (PPTs). However, a clear picture of depalmitoylation has not yet emerged, in part because the enzyme-substrate relationships and specific functions of depalmitoylation are only beginning to be uncovered. Further, despite the finding that loss-of-function mutations affecting palmitoyl-protein thioesterase 1 (PPT1) function cause a severe pediatric neurodegenerative disease, the role of PPT1 as a depalmitoylase has attracted relatively little attention. Understanding the role of depalmitoylation by PPT1 in neuronal function is a fertile area for ongoing basic science and translational research that may have broader therapeutic implications for neurodegeneration. Here, we will briefly introduce the rapidly growing field surrounding protein palmitoylation and depalmitoylation, then will focus on the role of PPT1 in development, health, and neurological disease.

Identification of synaptic PPT1 substrates highlight roles of depalmitoylation in disulfide bond formation and synaptic function

“…This finding correlates with the "Synaptogenesis signaling pathway" identified by IPA as impacted by palmitoylation in PPT1 KO (Figure 4C), as well as previous findings on the importance of NrCAM palmitoylation for neuronal morphogenesis (Ponimaskin et al, 2008). The aberrant palmitoylation of IgG-class adhesion molecule substrates may explain previously-described post-synaptic deficits, including immature dendritic spine morphology of cultured neurons (Koster and Yoshii, 2019;Sapir et al, 2019). Additional research on adhesion molecule depalmitoylation in development may elucidate whether these changes are due to failed cis/trans assembly.…”

“…Due to its link to NCL and lysosomal storage diseases more broadly, PPT1 depalmitoylation activity has long been considered necessary for protein degradation (Koster and Yoshii, 2019;Lu et al, 1996). The original description of cellular phenotypes of CLN1 included the accumulation of lipid modified cysteine-containing peptides/proteins in patient-derived lymphocytes and skin fibroblasts (Hofmann et al, 1997;Lu et al, 1996).…”

Ileal proteomic changes associated with IL-25-mediated resistance against intestinal trematode infections

“…This supports that the processes related Infection of rIL-25-treated mice also induced reduction in the production of palmitoyl-protein thiosterase (PPT). Protein thioestherases, or depalmitoylases, mediate the depalmitoylation of modified proteins, thereby completing a cycle of this reversible post-translational modification [61][62][63]. Palmitoylation can effectively act as a post-translational "switch" on some proteins and provide dynamic control over protein localization or function.…”

Ileal proteomic changes associated with IL-25-mediated resistance against intestinal trematode infections

“…Infection of rIL-25-treated mice also induced reduction in the production of palmitoyl-protein thiosterase (PPT). Protein thioestherases, or depalmitoylases, participate the depalmitoylation of altered proteins, thus completing a cycle of this reversible post-translational modification [61][62][63]. Palmitoylation act as a post-translational "switch" on several proteins providing a dynamic control on protein localization or function.…”