Fungal Ice2p Has Remote Homology to SERINCs, Restriction Factors for HIV and Other Viruses

Abstract

Ice2p is an integral endoplasmic reticulum (ER) membrane protein in budding yeast S. cerevisiae named “ICE” because its deletion reduces inheritance of cortical ER. Ice2p has also been reported to be involved in mobilising neutral lipids from lipid droplets to the ER for phospholipid metabolism. In addition, it has been proposed that Ice2 acts as a tether that links the ER both to lipid droplets and to the plasma membrane, via a long cytoplasmic loop that contains multiple predicted amphipathic helices. We used bioinformatics to study Ice2p. First, regarding its topology, we found that members of the Ice2 family in diverse fungi are predominantly predicted to have ten transmembrane helices, casting doubt on the prediction of eight transmembrane helices for the yeast protein. Applying the dominant topology to Ice2p puts the loop with amphipathic helices is in the lumen of the ER, not the cytoplasm, so unable to tether. Secondly, we looked for homologues of Ice2p using the profile-profile search tool HHpred and supporting results with bespoke PSI-BLAST searches. This identified a strong homology to SERINCs (serine incorporators), ten transmembrane helix proteins found universally in eukaryotes. Since SERINCs are potent restriction factors for HIV and other viruses, study of Ice2p may reveal functions shared with SERINCs, including antiviral (including anti-HIV) restriction mechanisms.