Function of the Golgi apparatus in protein maturation
The most important subcellular structure in the context of wrinkly skin syndrome (WSS), is the Golgi apparatus. The Golgi apparatus is an important part of the endomembrane system because it processes proteins and lipids prior to their delivery to the plasma membrane and/or secretion into the extracellular environment. The Golgi is organized into a polarized series of membrane-bound stacks, called cisternae, through which proteins are trafficked in sequence once they leave the endoplasmic reticulum (ER), where the proteins and lipids are synthesized. Proteins destined for secretion or delivery to the plasma membrane arrive first at the cis-Golgi, before being trafficked through the medial and trans-Golgi. In the Golgi, proteins undergo extensive post-translational modifications (PTMs). In the context of WSS, the most significant PTM events are the glycosylation of proteins comprising the extracellular matrix (ECM) of epidermal cells. The two types of glycosylation events in the Golgi are N-linked glycosylation and O-linked glycosylation. Glycosylation of proteins destined for secretion occurs through the forward movement of proteins throughout the Golgi apparatus. The proteins destined for secretion are then trafficked to the plasma membrane in secretory vesicles. Retrograde (backward) transport in the Golgi apparatus is also important. In order to retain the enzymes responsible for protein glycosylation in the correct regions of the Golgi, there must be retrograde transport of these enzymes back into the Golgi apparatus.
In addition, retrograde transport serves a quality control function, by shuttling misfolded proteins back into the ER or retaining them within the Golgi itself until proper protein folding and maturation is completed. The activity of protein-modifying enzymes, like glycosyltransferases and glycosidases, relies on the lumenal pH of the Golgi apparatus. Cisternal pH becomes increasingly acidic (lower pH) with progression from cis- to trans- regions of the Golgi. Disruption of decreasing pH can impart significant effects on the efficiency and sequence of glycosylation events. Maintenance of the pH gradient across the Golgi is instrumental for proper post-translational modification of proteins prior to secretion. Retrograde transport and pH regulation are therefore vital to the proper functioning of the Golgi apparatus. Genetic causes of WSS
Patients with both missense and/or nonsense mutations of the ATP6V0A2 gene have been shown to phenotypically express wrinkly skin syndrome (WSS) or autosomal recessive cutis laxa type II (ARCL II) (another cutis laxa disorder). Some consider WSS to be a milder variant of ARCL II, but the genetic causes of WSS are not yet known. A large number of patients with WSS and ARCL II show a loss-of-function in the a2-subunit. These mutations in ATP6V0A2 are associated with defective glycan biosynthesis and defective Golgi apparatus structure. However, the exact mechanism of how mutations in the ATP6V0A2 gene lead to these effects is unclear. Aberrant Golgi functioning and clinical symptoms of WSS
WSS is characterized by defects in the elastic fiber system that comprises the extracellular matrix of epidermal cells.