Subcellular Trafficking of Mammalian Lysosomal Proteins: An Extended View

Abstract

Lysosomes clear macromolecules, maintain nutrient and cholesterol homeostasis, participate in tissue repair, and in many other cellular functions. To assume these tasks, lysosomes rely on their large arsenal of acid hydrolases, transmembrane proteins and membrane-associated proteins. It is therefore imperative that, post-synthesis, these proteins are specifically recognized as lysosomal components and are correctly sorted to this organelle through the endosomes. Lysosomal transmembrane proteins contain consensus motifs in their cytosolic regions (tyrosine- or dileucine-based) that serve as sorting signals to the endosomes, whereas most lysosomal acid hydrolases acquire mannose 6-phosphate (Man-6-P) moieties that mediate binding to two membrane receptors with endosomal sorting motifs in their cytosolic tails. These tyrosine- and dileucine-based motifs are tickets for boarding in clathrin-coated carriers that transport their cargo from the trans-Golgi network and plasma membrane to the endosomes. However, increasing evidence points to additional mechanisms participating in the biogenesis of lysosomes. In some cell types, for example, there are alternatives to the Man-6-P receptors for the transport of some acid hydrolases. In addition, several “non-consensus” sorting motifs have been identified, and atypical transport routes to endolysosomes have been brought to light. These “unconventional” or “less known” transport mechanisms are the focus of this review.

Non-Canonical Binding of a Small Molecule to Sortilin Alters Cellular Trafficking of ApoB and PCSK9 in Liver Derived Cells

“…6A). When we ran the same diC8-PI(3,4,5)P 3 concentration curves in the presence of 10 µM cpd541 and 10 µM cpd984, we found that cpd541 abolished PI(3,4,5)P 3 We previously showed that circulating VLDL contains more PI(3,4,5)P 3 than LDL 17 . Using these same fractions, we characterized rat derived circulating VLDL and LDL binding to Sortilin using SPR and MST.…”

“…Vps10 orthologue Sortilin in mammals traffics proteins from the Golgi where it is activated by furin mediated cleavage of its prodomain 2 . Sortilin is responsible for trafficking its ligands between secretory pathways and lysosomal protein pathways 3 . Vps10 and its mammalian counterpart Sortilin release cargo upon entering acidic endosomal compartments, which may be followed by dimerization of the luminal b-propeller domains of Sortilin.…”

Functional characterization of germline variants in theTMEM127tumor suppressor reveals novel insights into its membrane topology and trafficking

“…We then scanned the C-terminal of TMEM127 for potential tyrosine-based motifs (YXXΦ), where X is any amino acid and Φ is a bulky, hydrophobic acid (F,I,L,M or V), and [34][35][36] . Although these are considered to be the two classical motifs, as signaling motifs can be diverse, we also considered other less common variations such as extended-acidic, dileucine-based, endocytic motifs [37][38][39][40][41] .…”

Molecular interplay of autophagy and endocytosis in human health and diseases

“…The presence of various sorting signals is essential for recruiting the sorting machinery, beginning with the mono‐ubiquitination of single or multiple lysine residues on the receptor tyrosine kinases (RTKs) (Jovic et al , ). Tyrosine and di‐leucine motifs are required for clathrin‐mediated transport from vesicles to endosomes and lysosomes (Staudt, Puissant & Boonen, ). Two microdomains of early endosomes, including the tubular endosomal network (TEN) and vacuolar domain, contribute towards the sorting process.…”

“…The transmembrane proteins involved in endocytic pathways are synthesized in the ER, and may either be directly sorted from the TGN to the endosomes or sorted to the cell surface from which they associate with endocytic pathways. Classical endosomal sorting is mostly dependent on clathrin‐coated vesicles (CCVs) (Robinson, ; Staudt et al , ). Clathrin has a pivotal role in many cellular processes such as endosomal sorting complex required for transport (ESCRT)‐dependent cargo sorting to endosomes, mitosis, and secretory protein transport from the TGN (McMahon & Boucrot, ).…”