Functional significance of globotriaosyl ceramide in interferon-α2/type 1 interferon receptor-mediated antiviral activity
✍ Scribed by Aye-Aye Khine; Clifford A. Lingwood
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 367 KB
- Volume
- 182
- Category
- Article
- ISSN
- 0021-9541
No coin nor oath required. For personal study only.
✦ Synopsis
The N-terminus of the type 1 interferon receptor subunit, IFNAR1, has high amino acid sequence similarity to the receptor binding B subunit of the Escherichia coli-derived verotoxin 1, VT1. The glycolipid, globotriaosyl ceramide (Gb 3 : Gal ␣ 1 3 4 Gal  1 3 4 Glu  1 3 1 Cer) is the specific cell receptor for VT1. Gb 3 -deficient variant cells selected for VT resistance are cross-resistant to interferon-␣ (IFN-␣)-mediated antiproliferative activity. The association of eIFNAR1 with Gal ␣ 1 3 4 Gal containing glycolipids has been previously shown to be important for the receptor-mediated IFN-␣ signal transduction for growth inhibition. The crucial role of Gb 3 for the signal transduction of IFN-␣-mediated antiviral activity is now reported. IFN-␣-mediated antiviral activity, nuclear translocation of activated Stat1, and increased expression of PKR were defective in Gb 3 -deficient vero mutant cells, although the surface expression of IFNAR1 was unaltered. The VT1B subunit was found to inhibit IFN-␣-mediated antiviral activity, Stat1 nuclear translocation and PKR upregulation. Unlike VT1 cytotoxicity, IFN-␣-induced Stat1 nuclear translocation was not inhibited when RME was prevented, suggesting that the accessory function of Gb 3 occurs at the plasma membrane. IFN-␣ antiviral activity was also studied in Gb 3 -positive MRC-5 cells, which are resistant to IFN-␣ growth inhibition, partially resistant to VT1 but still remain fully sensitive to IFN-␣ antiviral activity, and two astrocytoma cell lines expressing different Gb 3 fatty acid isoforms. In both systems, long chain fatty acid-containing Gb 3 isoforms, which are less effective to mediate VT1 cytotoxicity, were found to correlate with higher IFN-␣-mediated antiviral activity. Inhibition of Gb 3 synthesis in toto prevented IFN-␣ antiviral activity in all cells. We propose that the long chain Gb 3 fatty isoforms preferentially remain in the plasma membrane, and by associating with IFNAR1, mediate IFN-␣ antiviral signaling, whereas short chain Gb 3 fatty acid isoforms are preferentially internalized to mediate VT1 cytotoxicity and IFNAR1-dependent IFN-␣ growth inhibition.