Elsevier

Matrix Biology

Volume 20, Issue 8, December 2001, Pages 499-508
Matrix Biology

Mini review
The six hyaluronidase-like genes in the human and mouse genomes

https://doi.org/10.1016/S0945-053X(01)00172-XGet rights and content

Abstract

The human genome contains six hyaluronidase-like genes. Three genes (HYAL1, HYAL2 and HYAL3) are clustered on chromosome 3p21.3, and another two genes (HYAL4 and PH-20/SPAM1) and one expressed pseudogene (HYALP1) are similarly clustered on chromosome 7q31.3. The extensive homology between the different hyaluronidase genes suggests ancient gene duplication, followed by en masse block duplication, events that occurred before the emergence of modern mammals. Very recently we have found that the mouse genome also has six hyaluronidase-like genes that are also grouped into two clusters of three, in regions syntenic with the human genome. Surprisingly, the mouse ortholog of HYALP1 does not contain any mutations, and unlike its human counterpart may actually encode an active enzyme. Hyal-1 is the only hyaluronidase in mammalian plasma and urine, and is also found at high levels in major organs such as liver, kidney, spleen, and heart. A model is proposed suggesting that Hyal-2 and Hyal-1 are the major mammalian hyaluronidases in somatic tissues, and that they act in concert to degrade high molecular weight hyaluronan to the tetrasaccharide. Twenty-kDa hyaluronan fragments are generated at the cell surface in unique endocytic vesicles resulting from digestion by the glycosylphosphatidyl-inositol-anchored Hyal-2, transported intracellularly by an unknown process, and then further digested by Hyal-1. The two β-exoglycosidases, β-glucuronidase and β-N-acetyl glucosaminidase, remove sugars from reducing termini of hyaluronan oligomers, and supplement the hyaluronidases in the catabolism of hyaluronan.

Introduction

The hyaluronidases from vertebrate somatic tissues, despite their importance, have until now defied explication. They are difficult to purify, present at exceedingly low concentrations, and have very high but unstable specific activities in the absence of detergents and protease inhibitors. The recent purification of Hyal-1 (Frost et al., 1997), the first somatic hyaluronidase to be isolated, and the explosion of information that resulted from the human genome project, facilitated rapid accumulation of new knowledge. It is now recognized that the hyaluronidases are a family of enzymes. There are six hyaluronidase-like sequences in the human genome (Csoka et al., 1999), clustered in groups of three at two chromosomal sites, on chromosomes 3p21.3 (HYAL1, HYAL2 and HYAL3) and 7q31.3 (HYAL4, PH20/SPAM1 and HYALP1). HYALP1 is an expressed pseudogene in humans. A disorder resulting from a mutation in HYAL1 has recently been identified and termed Mucopolysaccharidosis IX (Natowicz et al., 1996).

Section snippets

Hyal-1, plasma hyaluronidase

The acid-active hyaluronidase in serum had been recognized for decades (De Salegui and Pigman, 1967) but has defied isolation until recently. With the development of rapid new assays (Stern and Stern, 1992, Guntenhoener et al., 1992, Frost et al., 1997), and the recognition that the activity was unstable in the absence of detergents, the serum enzyme was finally isolated. It was the first hyaluronidase to be purified to homogeneity from mammalian somatic tissues. It was then cloned, sequenced,

Genomic arrangement of the six hyaluronidase paralogs

The sequence of the gene for human Hyal-1 facilitated a screen of expressed sequence tag (EST) databases. This analysis revealed that the human genome contains six paralogous hyaluronidase-like sequences with approximately 40% identity to each other. They are grouped into two tightly-linked triplets on human chromosomes 3p21.3 and 7q31.3 (Fig. 2), an arrangement that probably arose from two gene duplication events followed by cluster-block duplication at some time before the emergence of modern

Enzymology and cell biology of HA degradation: proposal of a hypothetical model

Hyaluronan has a surprisingly rapid rate of turnover for such a voluminous macromolecule. Circulating levels of HA rise rapidly in response to acute stress, in shock, septicemia, extensive burns, and in sepsis. Such increases in HA are probably survival mechanisms. Hyaluronan takes on water of hydration resulting in a solvent domain 10 000 times the original polymer volume. Hyaluronan may function as an intravascular volume expander preventing circulatory collapse.

High levels of HA are present

Mucopolysaccharidosis IX (MPS IX): Hyal-1 deficiency

Genetic deficiencies of the different hyaluronidase enzymes could result in clinically distinct syndromes. Deficiency of the human plasma hyaluronidase, Hyal-1, has been reported, and termed Mucopolysaccharidosis IX (Natowicz et al., 1996, Triggs-Raine et al., 1999). The patient has a remarkably normal phenotype. There is some growth retardation (5th percentile), bilateral peri- and intra-articular soft tissue masses, transient painful swelling of these masses with occasional effusions, and

The role of hyaluronidases in cancer

Hyaluronan has been invoked as mechanisms for tumor invasion and metastatic spread. The levels of HA surrounding tumor cells often correlate with tumor aggressiveness and poor outcome (Zhang et al., 1995). Overproduction of HA enhances anchorage-independent tumor cell growth (Kosaki et al., 1999, Liu et al., 2001). Loss of hyaluronidase activity, permitting accumulation of HA, may be one of the several steps required by cells in the multi-step process of carcinogenesis. Hyaluronidases would

Unanswered questions and concluding remarks

Details of the catabolic mechanisms involved in HA catabolism remain elusive. It is not known why there is an acid-active hyaluronidase in the circulation and in urine. Moreover, the absence of a circulating catalytically active hyaluronidase in some species poses clear questions as to its function (Fiszer-Szafarz, 1984). In cultured cells, whether stromal or epithelial, most hyaluronidase activity is quickly secreted into the culture medium and is not retained by the cell layer. Does this

Acknowledgements

Supported by grants from the N.I.H., P50 DE/CA11912, and the Scleroderma Foundation to R.S.

References (32)

  • M.F. Meyer et al.

    The soluble hyaluronidase from bull testes is a fragment of the membrane-bound PH-20 enzyme

    FEBS Lett.

    (1997)
  • S. Stair-Nawy et al.

    Hyaluronidase expression in human skin fibroblasts

    Biochem. Biophys. Res. Commun.

    (1999)
  • M. Stern et al.

    An ELISA-like assay for hyaluronidase and hyaluronidase inhibitors

    Matrix

    (1992)
  • R.H. Tammi et al.

    Hyaluronan enters keratinocytes by a novel endocytic route for catabolism

    J. Biol. Chem.

    (2001)
  • S. Banerji et al.

    LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan

    J. Cell Biol.

    (1999)
  • J. Felsenstein

    PHYLIP — phylogeny inference package (Version3.2)

    Cladistics

    (1989)
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