Regulatory mechanisms of the retromer-WASH complex in endosomal recycling

초록

Many mutations and genetic variances underlying neurological diseases have been recently determined through massive human DNA sequencing studies. Remarkably, many neurological disorders are caused by mutations in genes coding endosomal proteins which maintain cellular homeostasis by sorting, recycling, and degrading endocytosed cargoes. Thus, the molecular mechanism linking deregulation of endosomal trafficking to onset of neurological disorders needs to be elucidated. The SNX27-retromer complex regulates endosomal recycling of SNX27-interacting proteins such as G-protein-coupled receptors (?2-adrenergic receptor and parathyroid hormone receptor), ion channels (potassium channels and glucose transporter 1), and ionotrophic glutamate receptors (NMDA and AMPA receptors) which are crucial for signal transduction, neuronal plasticity and metabolite transport. However, mechanisms for how the retromer complex specifies destinations of each cargo remain unclear. In the talk, I will discuss the molecular mechanism of the SNX-retromer complex in regulating its cargo transport. SNX27 directly interacts with FAM21, which also binds to retromer, within the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex. This interaction is required for the precise localization of SNX27 at an endosomal subdomain and recycling of SNX27-retromer cargoes. Furthermore, FAM21 prevents cargo transport to the Golgi apparatus by controlling levels of phosphatidylinositol 4-phosphate, which facilitates cargo dissociation at the Golgi apparatus. Taken together, these results demonstrate that the SNX27-retromer-WASH complex acts as a hub to direct cargoes to the plasma membrane by blocking their transport to lysosomes and the Golgi apparatus. The finding would help us understand cellular mechanisms underlying the neurological disorders.