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Lysosomal multienzyme complex: pros and cons of working together

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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.

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Abbreviations

ASMC:

Aortic smooth muscle cell

BiP:

Binding immunoglobulin protein

β-GAL:

β-Galactosidase

BM:

Bone marrow

CHOP:

CCAAT/enhancer-binding protein homologous protein

CMA:

Chaperone-mediated autophagy

EBP:

Elastin-binding protein

ECM:

Extracellular matrix

EMH:

Extramedullary hematopoiesis

ER:

Endoplasmic reticulum

GALNS:

N-acetylgalactosamine-6-sulfate sulfatase

GEMs:

Glysosphingolipid-enriched microdomains

GM1:

GM1-gangliosidosis

GPCR:

Guanine protein-coupled receptor

GS:

Galactosialidosis

Hsp:

Heat shock protein

IGF-1R:

Insulin-like growth factor 1 receptor

IP3R:

Inositol trisphosphate receptor

JNK:

c-Jun N-terminal kinases

LAMP:

Lysosomal membrane-associated protein

LM:

Lysosomal membrane

LMC:

Lysosomal multienzyme complex

LPS:

Lipopolysaccharide

LSD:

Lysosomal storage disorder

MAMs:

Mitochondria-associated ER membranes

MAPK/ERK:

Mitogen-activated protein kinase

MAP2K/MEK:

Mitogen-activated protein kinase kinase

MPP:

Metalloproteinase

MyD88:

Myeloid differentiation primary response gene (88)

NEU1:

Neuraminidase-1

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PDGF-R:

Platelet-derived growth factor receptor

PI3K:

Phosphoinositide 3-kinase

PLCγ:

Phospholipase C gamma

PM:

Plasma membrane

PPCA:

Protective protein/cathepsin A

Ras:

Rapidly accelerated fibrosarcoma

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

UPR:

Unfolded protein response

VCAM1:

Vascular cell adhesion molecule 1

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Acknowledgments

We thank Dr. Angela McArthur for editing this manuscript. A.d’A. holds the Jewelers for Children Endowed Chair in Genetics and Gene Therapy. Work from d’Azzo’s laboratory that is included in this review was supported by the National Institutes of Health (NIH) grants GM60905 and DK52025, the Assisi Foundation of Memphis, the American Lebanese Syrian Associated Charities (ALSAC) and the National Tay-Sachs & Allied Disease Association (NTSAD).

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Authors and Affiliations

  1. Department of Genetics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA

    Ida Annunziata & Alessandra d’Azzo

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA

    Erik J. Bonten

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  1. Erik J. Bonten
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  2. Ida Annunziata
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  3. Alessandra d’Azzo
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Correspondence to Alessandra d’Azzo.

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Bonten, E.J., Annunziata, I. & d’Azzo, A. Lysosomal multienzyme complex: pros and cons of working together. Cell. Mol. Life Sci. 71, 2017–2032 (2014). https://doi.org/10.1007/s00018-013-1538-3

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  • DOI: https://doi.org/10.1007/s00018-013-1538-3

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