Abstract
Protein homeostasis is maintained by removing misfolded, damaged, or excess proteins and damaged organelles from the cell by three major pathways; the ubiquitin-proteasome system, the autophagy-lysosomal pathway, and the endo-lysosomal pathway. The requirement for ubiquitin provides a link between all three pathways. Sorting nexins are a highly conserved and diverse family of membrane-associated proteins that not only traffic proteins throughout the cells but also provide a second common thread between protein homeostasis pathways. In this review, we will discuss the connections between sorting nexins, ubiquitin, and the interconnected roles they play in maintaining protein quality control mechanisms. Underlying their importance, genetic defects in sorting nexins are linked with a variety of human diseases including neurodegenerative, cardiovascular diseases, viral infections, and cancer. This serves to emphasize the critical roles sorting nexins play in many aspects of cellular function.
Highlights
Maintenance of homeostasis is handled by sophisticated quality control systems that ensure that malformed or excess proteins are degraded at the appropriate time and location
Selective proteolysis is largely mediated by the ubiquitin-proteasomal system (UPS) and the autophagy-lysosomal pathway (ALP)
The sorting nexin (SNX)-phox homology (PX) subfamily consists only of a PX domain. This family includes SNX3 which binds to a multi-protein complex called the retromer that consists of three conserved subunits (VPS26, VPS29, and VPS35) [30,31,32]
Summary
Selective proteolysis is largely mediated by the ubiquitin-proteasomal system (UPS) and the autophagy-lysosomal pathway (ALP). Proteins can be retrieved from this degradative fate and selected for enrichment in endosomal “retrieval” subdomains, namely the trans-Golgi network (TGN), or recycling endosomes From here they are recycled back to the plasma membrane by the secretory pathway [12,14]. Initially reported as independent pathways, the UPS and ALP are known to be interconnected, linked by their common requirement for ubiquitin in substrate targeting Another common thread is that they all utilize the evolutionarily conserved sorting nexin (SNX) family of proteins to move substrates to different destinations (Figure 1). In the autophagy-lysosome pathway (ALP) cargos are sequestered to the vacuole by double-membraned vesicles called autophagosomes by selective or non-selective mechanisms.
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