Palmitoylation Regulates Epidermal Homeostasis and Hair Follicle Differentiation

Abstract

Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE) and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear β-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis.

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

“…15,23 The dynamic acylation cycle can be regulated by different physiological stimuli that contribute to cellular homeostasis and plasticity. 24,25 Attachment of an acyl moiety by protein acyltransferases results in the shifting of protein substrates from endoplasmic reticulum or Golgi apparatus to the PM. On the contrary, removal of an acyl moiety by acyl protein thioesterase increases the trapping of the protein in intracellular compartments, causing the proteins to possibly be degraded through an ubiquitin-proteasome-dependent pathway.…”

Protein palmitoylation and subcellular trafficking

“…A few selected examples of myristoylated plus palmitoylated human proteins are shown in Box 2. Several palmitoyl transferases of the DHHC family are known to increase palmitate transfer to previously myristoylated protein substrates [19]: that is the case for eNOS [46], Giα2 [47], Fyn [48] and Lck kinase [49].…”

Chemoproteomics reveals Toll-like receptor fatty acylation

“…This method is commonly used to identify DHHCs capable of modifying individual protein substrates [35,[50][51][52][53]. CD86-HA S-palmitoylation was increased by DHHCs 2, 3, 6 and 7 ( Figure 2D, Additional file 2: Figure S7).…”