ReviewHyaluronidase 2 and its intriguing role as a cell-entry receptor for oncogenic sheep retroviruses
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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Hyaluronidase-2 Regulates RhoA Signaling, Myofibroblast Contractility, and Other Key Profibrotic Myofibroblast Functions
2020, American Journal of PathologyThe human endogenous retrovirus K(HML-2) has a broad envelope-mediated cellular tropism and is prone to inhibition at a post-entry, pre-integration step
2016, VirologyCitation Excerpt :Murine TfR1 (mTfR1) and human Hyal2 (huHyal2) were used as positive controls for the entry of pseudotypes carrying MMTV and JSRV envelope proteins. JSRV is able to use the human Hyal2 for entry (Miller, 2008) but human TfR1 cannot be used by MMTV (Wang et al., 2008a) and was therefore used as a negative control. To test whether TfR1-V5 expression increases HML-2 entry into HEK 293T, cells were transfected with plasmid DNA encoding hTfR1, fTfR1 or mTfR1 or with plasmids expressing cHyal2 or hHyal2.
Hyal2 is a glycosylphosphatidylinositol-anchored, lipid raft-associated hyaluronidase
2011, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Our observations support previous descriptions of Hyal2 at the cell surface [4,5,8,23–25] but not the suggestion that the majority of the protein resides in lysosomes [3] or the cytoplasm [6]. At the cell surface, Hyal2 would be well poised to exert the various functions that have been demonstrated for this ubiquitous protein, i.e. cleave extracellular or pericellular HA into biologically active (angiogenic, inflammatory) fragments [9,19,20], interact with tumor growth factor-β and mediate some of its intracellular actions [24], act as a receptor for ovine oncogenic retroviruses [25], and, for platelet Hyal2, cleave the extracellular HA cables that bind leukocytes [8]. In tumor cells, Hyal2 may be associated with the process of intravasation [23].
Reactive oxygen species and hyaluronidase 2 regulate airway epithelial hyaluronan fragmentation
2010, Journal of Biological ChemistryCitation Excerpt :In airway epithelial cells, CD44 is localized in the basolateral compartment, and thus, unlikely to participate in Hyal2 activity regulation. Perhaps other proteins or cofactors might also modulate Hyal2 and/or be required for Hyal2 activity (64). Knockdown studies using lentivirus-expressing Hyal2-shRNA confirmed that Hyal2 is up-regulated under oxidative stress.
Pathology and Pathogenesis of Ovine Pulmonary Adenocarcinoma
2010, Journal of Comparative PathologyCitation Excerpt :Recent cell culture studies have begun to examine the details of JSRV replication and some notable features that are relevant to pathogenesis are worth highlighting here: The receptor used by JSRV is hyaluronidase 2 (Hyal2), a glycosylphosphatidylinositol-anchored protein that is present on the surface of many cell types and is not restricted to lung epithelial cells (Rai et al., 2001; Miller, 2008). JSRV therefore has the potential to enter and infect a range of different cells and tissues in addition to lung epithelial cells, including lymphocytes and macrophages (Holland et al., 1999).