Abstract
Aberrations in membrane trafficking pathways have profound effects in cellular dynamics of cellular sorting processes and can drive severe physiological outcomes. Sorting nexin 27 (SNX27) is a metazoan-specific sorting nexin protein from the PX-FERM domain family and is required for endosomal recycling of many important transmembrane receptors. Multiple studies have shown SNX27-mediated recycling requires association with retromer, one of the best-known regulators of endosomal trafficking. SNX27/retromer downregulation is strongly linked to Down’s Syndrome (DS) via glutamate receptor dysfunction and to Alzheimer’s Disease (AD) through increased intracellular production of amyloid peptides from amyloid precursor protein (APP) breakdown. SNX27 is further linked to addiction via its role in potassium channel trafficking, and its over-expression is linked to tumorigenesis, cancer progression, and metastasis. Thus, the correct sorting of multiple receptors by SNX27/retromer is vital for normal cellular function to prevent human diseases. The role of SNX27 in regulating cargo recycling from endosomes to the cell surface is firmly established, but how SNX27 assembles with retromer to generate tubulovesicular carriers remains elusive. Whether SNX27/retromer may be a putative therapeutic target to prevent neurodegenerative disease is now an emerging area of study. This review will provide an update on our molecular understanding of endosomal trafficking events mediated by the SNX27/retromer complex on endosomes.
Highlights
Cells communicate with the extracellular environment via cell surface transmembrane proteins that direct processes such as nutrient uptake, cellular adhesion, and intracellular signal transduction
We provide an update on the current understanding of Sorting nexin 27 (SNX27)/retromer biology with focus on molecular details and the link between SNX27 and retromer in sorting critical cargoes required for human health
SNX27 acts as a major trafficking regulator through binding post-synaptic density 95/discs large/zonula occludens-1 (PDZ) cargo in mammalian cells (Cao et al, 1999; Lauffer et al, 2010; Temkin et al, 2011; Steinberg et al, 2013; Gallon et al, 2014)
Summary
Cells communicate with the extracellular environment via cell surface transmembrane proteins that direct processes such as nutrient uptake, cellular adhesion, and intracellular signal transduction Homeostasis of these molecules is precisely controlled by balancing exocytic, endocytic, and intracellular trafficking pathways. Many critical transmembrane proteins and lipids must be internalized, while others undergo selective sorting, either through recycling to the cell surface or trafficking to lysosomes for downregulation or degradation. The endocytic network regulates both structural and functional synaptic remodeling by controlling the trafficking of numerous transmembrane proteins cargoes; examples include cell adhesion molecules, receptors required in signaling pathways, and ion channels (Anggono and Huganir, 2012; Di Fiore and von Zastrow, 2014). We provide an update on the current understanding of SNX27/retromer biology with focus on molecular details and the link between SNX27 and retromer in sorting critical cargoes required for human health
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