Toward Understanding the Molecular Role of SNX27/Retromer in Human Health and Disease

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.

SNX27–Retromer directly binds ESCPE-1 to transfer cargo proteins during endosomal recycling

“…Overall, in defining the mechanistic basis of SNX27–Retromer association with ESCPE-1, we have provided new functional insight into the endosomal sorting of hundreds of internalized PDZbm-containing receptors, channels, transporter, enzymes, and adhesion molecules for repopulation of the cell surface [ 13 ]. This increased molecular understanding provides new insight into the role of sequence-dependent endosome sorting in cellular processes ranging from the establishment of polarity and the uptake of nutrients through to synaptic function and cancer cell metastasis in both health and disease [ 40 ].…”

“…It is from these subdomains that further membrane remodeling ensues to drive the biogenesis of cargo-enriched tubular profiles and tubulovesicular carriers that physically transport cargo back to the cell surface. Importantly, defects in SNX27–Retromer function are associated with the pathoetiology of human disease most notable neurological disorders and neurodegenerative disease [ 40 ].…”

Endosomal Recycling Defects and Neurodevelopmental Disorders

“…Binding to SNX3 mediates the localization of retromer in the early endosome, while RAS-related protein RAB7-GTP localizes retromer in the late endosome. Sequence-specific cargo recognition of retromer is partly mediated by SNX27 [ 8 ]. SNX27 recognizes ΦxNPxpY or ΦxNxxpY as a sorting motif (where Φ is a hydrophobic residue and x is any residue) at the carboxy-terminal FERM-like domain.…”

Improved mammalian retromer cryo-EM structures reveal a new assembly interface

“…Retromer is thus well established as an evolutionarily conserved heterotrimer that binds different Sorting Nexin (SNX) proteins to mediate cargo sorting from phosphatidylinositol-3-phosphate (PtdIns3 P )-enriched endosomal membranes. Retromer binds multiple sorting nexin family members, including SNX-BARs, SNX3, and metazoan-specific SNX27 (reviewed recently in ( 10, 23, 24 )). The retromer heterotrimer (formerly called Cargo Selective Complex, or CSC) has been implicated in direct cargo recognition in both mammalian cells ( 2, 25 ) and yeast ( 1, 26 ).…”

“…Mammalian retromer associates with the cytosolic face of endosomes, where it functions to recycle receptors, transporters, and adhesion molecules. Retromer is thought to mediate retrograde recycling to the trans -Golgi network (TGN) ( 1–3 ) or to the plasma membrane ( 4–7 ) through sorting into tubular-vesicular carriers (reviewed in ( 8– 10 )). Retromer-dependent cargoes undergo selective trafficking to avoid sorting to late endosomes and subsequent degradation in lysosomes ( 11 ), which ensures cells maintain homeostasis of transmembrane cargoes at the plasma membrane and within the endolysosomal system.…”