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.
Highlights
In the 1950s, Christian de Duve and colleagues made the peculiar observation that, when rat liver is homogenized in isotonic sucrose and fractionated into subcellular fractions by centrifugation, freezing/thawing of these fractions is required to get an accurate measurement of the total activity of several hydrolases with acidic pH optimums
Lysosomal transmembrane proteins contain consensus motifs in their cytosolic regions 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
Proteomic analyses have revealed that the lumen of lysosomes contains approximately 60 different acid hydrolases, and that the lysosomal membrane is spanned by many transmembrane proteins [3,4,5,6,7]
Summary
In the 1950s, Christian de Duve and colleagues made the peculiar observation that, when rat liver is homogenized in isotonic sucrose and fractionated into subcellular fractions by centrifugation, freezing/thawing of these fractions is required to get an accurate measurement of the total activity of several hydrolases with acidic pH optimums. Proteomic analyses have revealed that the lumen of lysosomes contains approximately 60 different acid hydrolases, and that the lysosomal membrane is spanned by many transmembrane proteins [3,4,5,6,7] These include structural proteins, a transmembrane vATPase complex that generates an intraluminal acidic environment in which acid hydrolases are active, as well as a large set of transporters that transfer the enzyme degradation products in the cytosol. The study of the underlying causes of lysosomal dysfunctions has pointed out that to maintain a well-oiled lysosomal machine and prevent deleterious cellular/tissue alterations, the cells must express all required lysosomal proteins but, most importantly, they need to efficiently and target them to the lysosomal compartment To meet this second requirement, the cells rely on several intracellular trafficking machineries that transport newly synthesized lysosomal membrane or soluble proteins to their residence site within the cells. We will only provide a brief description of the classical lysosomal sorting mechanisms for comparison purposes, as these have already been extensively discussed by others
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