Lysosomal multienzyme complex: pros and cons of working together

Abstract

The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, Protective Protein/Cathepsin A (PPCA), the sialidase, Neuraminidase-1 (NEU1), and the glycosidase β-Galactosidase (β-GAL). Next to this ‘core’ complex, the existence of sub-complexes, that may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1 and β-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders.

Biochemical and molecular characterization of novel mutations in GLB1 and NEU1 in patient cells with lysosomal storage disorders

“…Certain lysosomal proteins are functionally and physically associated as multiprotein complexes for efficient digestive reactions. One example of this type of complex consists of three core enzymes, b- 18), and mutations in any of these proteins lead to LSD pathology [2].…”

NEU1 Sialidase Regulates Membrane-tethered Mucin (MUC1) Ectodomain Adhesiveness for Pseudomonas aeruginosa and Decoy Receptor Release

“…Of the four known mammalian NEUs, NEU1 is the predominant sialidase expressed by human airway ECs, and the second most abundant, NEU3, is expressed at much lower levels (12). NEU1 is localized both to lysosomes and the cell surface (19) and is only active in association with its chaperone/transport protein, protective protein/cathepsin A (PPCA) (21). PPCA is a multipurpose protein that targets NEU1 to the lysosome and is absolutely required for proper folding, stability, oligomerization, and activation of NEU1 (21).…”

“…NEU1 is localized both to lysosomes and the cell surface (19) and is only active in association with its chaperone/transport protein, protective protein/cathepsin A (PPCA) (21). PPCA is a multipurpose protein that targets NEU1 to the lysosome and is absolutely required for proper folding, stability, oligomerization, and activation of NEU1 (21). We previously demonstrated intense NEU1 immunostaining at the superficial surface of the human airway epithelium, including the brush border of the trachea and bronchus (12).…”

Exploratory study of sublimed sulfur, in cognitively normal subjects and in Alzheimer’s dementia (AD) subjects: implications for Sulfur targeting Hydrogen sulfide (H2S)/Homocysteine (Hcy) and beta-galactosidase (GALAC)/Autophagy Signaling in AD

“…In aging , the phenomenon of lysosomal dysregulation reemerge in neurodegenerative disorders , reflecting epigenetic regulation of lysosome enzyme complexes. in both disorders [52]. In lysosomes, the degradation of complex, macromolecular substrates depends upon the synergistic action of multiple hydrolases working in a well-defined stepwise manner.…”