HYAL2, a Human Gene Expressed in Many Cells, Encodes a Lysosomal Hyaluronidase with a Novel Type of Specificity

Abstract

Using Expressed Sequence Tags (ESTs) deposited in the data banks, a cDNA has been assembled that encodes a protein related to the hyaluronidases from bee venom and mammalian sperm. Expression of this cDNA yielded a polypeptide termed HYAL2, which is located in lysosomes. The HYAL2 protein was shown to have hyaluronidase activity below pH 4. However, it only hydrolyzed hyaluronan of high molecular mass from umbilical cord, rooster comb, and a Streptococcus strain. The reaction product was a polysaccharide of about 20 kDa, which was further hydrolyzed to small oligosaccharides by the sperm hyaluronidase. Conversely, hyaluronan fragments from vitreous humor, which had a molecular mass of about 20 kDa, were not cleaved by the HYAL2 enzyme to any detectable extent. These results provide evidence for the existence of structural domains in hyaluronan, which are resistant to the action of this enzyme. The structural and functional implications of these findings are discussed.

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…HYAL2 (hyaluronidase 2, also known as LUCA2) is expressed at high levels in most tissues (including heart, placenta, lung, liver, skeletal muscle and kidney) but absent or poorly expressed in brain (Lepperdinger et al, 1998;Csoka et al, 1999;Lerman and Minna, 2000). Loss of expression in adult brain is reported to be due to promoter methylation (Lepperdinger et al, 2001).…”

“…The HYAL2 gene ( Figure 2a) encodes a 473 amino-acid protein ( Figure 2b) with a signal peptide (amino acids 1-20), and a calcium binding epidermal growth factor (EGF)-like domain (amino acids 365-469 by SMART prediction). Green fluorescent protein-tagged HYAL2 was shown to have a lysosomal localization (Lepperdinger et al, 1998), but subsequent work has suggested that HYAL2 is actually a cell surface glycosylphosphatidylinositol anchored protein (Rai et al, 2001). Although there is some evidence that it may also be produced in a soluble form.…”

“…It has been suggested that HA degradation occurs via a two-step process; first digestion of high-molecularweight HA to 20 kDa fragments, followed by a slower complete degradation (Csoka et al, 2001;Stern, 2004). HYAL2 has low (Lepperdinger et al, 1998;Vigdorovich et al, 2005), or even undetectable (Rai et al, 2001) hyaluronidase activity reported to be optimal pH 4.0 (Lepperdinger et al, 1998). It is thought that highmolecular-weight HA is tethered to the cell surface by CD44 and HYAL2, particularly in special microdomains (Bourguignon et al, 2004) through which the fragments can become internalized and digestion completed by HYAL1.…”

HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

“…Until recently, mammalian hyaluronidases were uncharacterized enzymatic activities present in many tissues, distinguished only on the basis of their pH optima. In the human, it is now established that at least six hyaluronidase-like sequences occur in the human genome, three each at two chromosomal locations: HYAL1, HYAL2, and HYAL3 at chromosome 3p21 (Lepperdinger et al, 1998; Cso ka et al, 1999); and HYAL4, SPAM1, and HYALP1 at chromosome 7q31 (Cso ka et al, 1999). The gene for Hyal-2, HYAL2, a recently identi®ed lysosomal hyaluronidase (Lepperdinger et al, 1998) resides immediately centromeric to HYAL1 on 3p21.3.…”

“…In the human, it is now established that at least six hyaluronidase-like sequences occur in the human genome, three each at two chromosomal locations: HYAL1, HYAL2, and HYAL3 at chromosome 3p21 (Lepperdinger et al, 1998; Cso ka et al, 1999); and HYAL4, SPAM1, and HYALP1 at chromosome 7q31 (Cso ka et al, 1999). The gene for Hyal-2, HYAL2, a recently identi®ed lysosomal hyaluronidase (Lepperdinger et al, 1998) resides immediately centromeric to HYAL1 on 3p21.3. Hyal-2 possesses an apparent speci®city for high molecular weight HA (420 kDa) and is expressed in all tissues except the brain.…”