Trafficking of lysosomal enzymes in normal and disease states.

Abstract

The lysosomal storage disorders constitute greater than 30 separate entities, the majority of which result from the absence of one or more lysosomal enzymes. While many of these disorders are due to the failure to synthesize an active form ofthe relevant enzyme, an increasing number ofcases are being reported where the defect lies in the inability to transport an active enzyme to the lysosome. Recent work from many laboratories has greatly enhanced our understanding ofhow newly synthesized lysosomal enzymes are segregated from secretory proteins and packaged into lysosomes. Studies of patients with defects in this sorting pathway have facilitated the unraveling of this complex process while also serving to pinpoint the exact site where the targeting has gone awry. The purpose of this review is to summarize our current understanding of lysosomal enzyme targeting and to discuss the defects in this pathway that have been documented thus far.Lysosomal enzymes, along with secretory proteins and plasma membrane proteins, are synthesized on membranebound polysomes in the rough endoplasmic reticulum (Fig. 1). Each of these proteins contains a hydrophobic amino terminal signal peptide which interacts with a signal recognition particle, an llS ribonucleoprotein, and thereby initiates the vectoral transport ofthe nascent protein across the endoplasmic reticulum membrane into the lumen of that organelle (1-3). Since lysosomal enzymes and secretory proteins share this mechanism for membrane translocation, they are mixed together in the lumen of the endoplasmic reticulum. The lysosomal enzymes (as well as most ofthe secretory and plasma membrane proteins) undergo cotranslational glycosylation of selected Asn residues. This glycosylation step involves the en bloc transfer ofa large preformed oligosaccharide (three glucose, nine mannose, and two N-acetylglucosamine residues) from a lipid-linked intermediate to the nascent polypeptide (4). In the endoplasmic reticulum, the signal peptide is cleaved, and the processing of the Asn-linked oligosaccharide begins by the excision of three glucoses and one of the mannose residues from the oligosaccharide.The proteins then move, by vesicular transport, to the Golgi stack where they undergo a variety of posttranslational modifications and are sorted for targeting to the proper destination, e.g., lysosome, secretory granule, or plasma membrane. During passage through the Golgi, the oligosaccharides on secretory and membrane glycoproteins are processed to sialic acid-containing complex-type units. While some of the oligosaccharides on lysosomal enzymes undergo similar processing, most undergo a Receivedfor publication 1I September 1985. different series of modifications. The critical modification is the acquisition of phosphomannosyl residues; these serve as the essential component ofa recognition marker which leads to binding to high affinity receptors (mannose-6-phosphate[M-6-P]' receptors) and subsequent translocation to lysosomes (5). This recognition marker is generated by the sequ...

Collectins — soluble proteins containing collagenous regions and lectin domains — and their roles in innate immunity

“…C-type lectins are extracellular proteins that bind to a variety of carbohydrates in a strictly Ca2+-dependent manner, whereas S-type lectins have no requirement for divalent cations; they occur both intra-and extracellularly and bind predominantly @-galactosides (Barondes, 1984;Liao et al, 1994). The main exceptions, in terms of carbohydrate binding proteins, which do not fit into either of these categories of lectins, are the extracellular proteins laminin and fibronectin (Yamada, 1983); the mannose-6-phosphate receptor (Kornfeld, 1986), responsible for targeting proteins to the lysosomal compartments; and the viral hemagglutinins (Wiley & Skehel, 1987). The pentraxin C-reactive protein (Kolb-Bachofen, 1991;Kottgen et al, 1992) and serum amyloid component P (SAP) (Kubak et al, 1988) also show lectin activities.…”

A Novel α-Helix in the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Is Critical for N-Glycan Polysialylation

“…The limited number of polysialylated proteins suggests that polysialylation is protein-specific and like other post-translational modifications of this type may require the polysialyltransferases to recognize their substrates by engaging in an initial protein-protein interaction. For example, the phosphotransferase, which catalyzes the first biosynthetic step in the synthesis of the mannose 6-phosphate tag for enzyme trafficking to the lysosome (23,24), recognizes a signal patch containing lysine residues on the lysosomal enzyme surface (25,26). Likewise, the GalNAc transferase that catalyzes the first step in the biosynthesis of the terminal GalNAc-4-SO 4 structure critical for the clearance of pituitary glycoprotein hormones (27), recognizes a cluster of basic residues in an ␣-helix positioned 6 -9 amino acids N-terminal to the N-glycan to be modified (28,29).…”

Increased Activity of Lysosomal Enzymes in the Peritoneal Fluid of Bacterial Peritonitis

“…T he precursors of the lysosomal enzymes are synthesized on ribosomes, 1 and their subsequent maturation and targeting to the final destination in lysosomes are directed by a sequence of recognition signals localized on the enzymes' molecule. [2][3][4] Approximately 5% to 20% of the mature lysosomal enzymes are secreted into the extracellular fluid before their delivery to lysosomes; subsequently, a portion of these enzymes bind to mannose 6-phosphate receptors on the surface of the cells, are internalized, and are delivered to lysosomes.…”