Review
Hyaluronidase 2 and its intriguing role as a cell-entry receptor for oncogenic sheep retroviruses

https://doi.org/10.1016/j.semcancer.2008.03.010Get rights and content

Abstract

Jaagsiekte sheep retrovirus (JSRV) causes lung adenocarcinoma in sheep and goats, while the closely related enzootic nasal tumor virus (ENTV) causes nasal tumors in the same species. The envelope (Env) protein from either virus can transform fibroblasts and epithelial cells in culture, indicating that the Env proteins are responsible for tumorigenesis. However, the primary function of retroviral Env proteins is to mediate virus entry into cells by interacting with specific cell-surface receptors, suggesting that the virus receptor might be a key player in transformation as well. Thus, identification of Hyaluronidase-2 (Hyal2) as the cell-entry receptor for both JSRV and ENTV suggested a role for Hyal2 in oncogenesis. Furthermore, Hyal2 is located in a key lung cancer tumor suppressor locus on chromosome 3p21.3, suggesting that Hyal2 might have a tumor suppressor activity that was disrupted by Env thereby leading to tumorigenesis. However, recent experiments showing that expression of the JSRV or ENTV Env protein in mouse lung can induce lung tumors, even though the viral Env proteins cannot bind to or utilize mouse Hyal2 as a receptor for virus entry into cells, indicate that Hyal2 plays no role in cancer induction by these retroviruses. Hyal2 remains an enigmatic member of the hyaluronidase family given its very low hyaluronidase activity in purified form or when expressed in cultured cells, suggesting that it may have evolved to perform some other as yet unknown function.

Section snippets

Oncogenic sheep retroviruses

Jaagsiekte sheep retrovirus (JSRV) causes pulmonary adenocarcinoma (also called sheep pulmonary adenomatosis or jaagsiekte) in sheep and goats [1]. JSRV-induced tumors arise from epithelial cells in the lower airway, and tumor cells express markers of type II alveolar and/or bronchiolar epithelial cells [2]. Two strains of a closely related retrovirus called enzootic nasal tumor virus (ENTV) have been cloned from sheep (ENTV-1) [3] and goats (ENTV-2) [4] that share ∼95% overall amino acid

Identification of Hyal2 as the cell-entry receptor for JSRV and ENTV

Retrovirus entry into cells depends on the presence of specific proteins that bind the viral Env protein and help trigger conformational changes in Env that lead to fusion of the virus and cell membranes and entry of the virus core into the cell. A wide variety of proteins have been found to serve as receptors for different retroviruses, based primarily on their ability to promote virus entry after expression in cells that are not naturally permissive for virus entry (Table 1). In most cases, a

Hyal2 location and enzymatic activity

Hyal2 was initially identified as a lysosomal hyaluronidase by addition of a green fluorescent protein (GFP) tag to the carboxy terminus of Hyal2 and by showing that GFP fluorescence localized to lysosomes after expression of the hybrid protein in a rat glioma cell line [14]. Hyal2 exhibited low but detectable hyaluronidase activity with an acidic pH optimum in these experiments. However, later studies have conclusively shown that Hyal2 is actually a glycosylphosphatidylinositol (GPI)-anchored

Hyal2 role in sheep retrovirus oncogenesis?

Interaction of JSRV and ENTV Env proteins with human Hyal2, location of the human Hyal2 gene in the 3p21.3 lung cancer tumor suppressor locus, and the presumed role of Hyal2 in metabolism of the extracellular matrix all pointed to a potential role of Hyal2 in transformation by the sheep retrovirus Env proteins. Support for this hypothesis was provided by studies in the human bronchial epithelial cell line BEAS-2B [22]. In these cells, Hyal2 can bind to the RON receptor tyrosine kinase rendering

Hyal2 role in sheep placental morphogenesis

Perhaps one of the most interesting findings relating to the interaction of sheep retrovirus Env proteins with Hyal2 is the role of Env proteins synthesized from endogenous sheep retroviruses and Hyal2 in placental morphogenesis in sheep. Mammals carry many copies of retroviruses in their genomes. Sheep carry ∼20 copies of endogenous retroviruses related to JSRV and ENTV, but the Env proteins synthesized from these viruses are either nonfunctional or contain mutations that render the Env

Acknowledgements

This work was supported by grants from the Fred Hutchinson Cancer Research Center and the National Institutes of Health.

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