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, which 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.

Fig. 1

Electron microscopy of Neu1 ^+/+ and Neu1 ^−/− macrophages shows lysosomes in Neu1 ^−/− cells that have fused with the PM and are being exocytosed (arrows). Adapted from a research originally published in Developmental Cell [54]. PM plasma membrane

Fig. 2

Schematic representation of the events that lead to loss of BM progenitors, splenic EMH, and loss of BM engraftment in sialidosis mice. BM bone marrow, EMH extramedullary hematopoiesis, LM lysosomal membrane, PM plasma membrane, SA hypersialylation, VCAM1 vascular cell adhesion molecule 1

Fig. 3

Electron microscopy of spinal cord neurons from β-gal ^+/+ and β-gal ^−/− mice (3 months of age) shows numerous enlarged lysosomes (L) in β-gal ^−/− neurons, which are filled with membranous material, ribosomes (R) and ER. Scale bars: upper panel 1 μm; lower panels 0.5 μm. Adapted from a study originally published in Molecular Cell [84]

Fig. 4

Schematic rendering of the molecular events in β-gal ^−/− neurons that occur downstream of G_M1 accumulation at the MAMs, leading to ER stress and mitochondria-mediated neuronal apoptosis. Adapted from a study originally published in Molecular Cell [93]

Fig. 5

Schematic representation of the pathways that involve the components of the LMC and the CSER and that become deregulated in case of single or combined enzyme deficiencies in sialidosis, GM₁, and GS. CMA chaperone-mediated autophagy, CSER cell surface elastin receptor, EBP elastin-binding protein, ECM extracellular matrix, LM lysosomal membrane, LMC lysosomal multienzyme complex, PM plasma membrane