Fungal Ice2p is in the same superfamily as 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.

Ice2 promotes ER membrane biogenesis in yeast by inhibiting the conserved lipin phosphatase complex

“…How could our findings from yeast apply to higher eukaryotes? Bioinformatic analysis suggests mammalian SERINC proteins as distant Ice2 orthologs (Alli‐Balogun & Levine, 2021), but whether SERINC proteins indeed have similar roles as Ice2 remains to be tested. In contrast, Nem1, Spo7, and Pah1 are evolutionarily conserved (Han et al , 2012).…”

Link between lipid remodeling and ESCRT-III function in multivesicular body formation

“…There are no obvious sequence identities between Vps55/Vps68 and Tms1, but a relatedness may be difficult to prove. This is exemplified by Ice2, which was recently identified as another SERINC member in yeast, only after extensive application of sophisticated bioinformatic tools (A lli-balogun and L evine 2021).…”

The Emerging Role of the Serine Incorporator Protein Family in Regulating Viral Infection

“…Furthermore, SERINC proteins were thought to have highly conserved sequences and no amino acid homology with other proteins (Grossman et al, 2000;Ren et al, 2014). However, in a recent report, Alli-Balogun et al identified Ice2p as a full-length homolog of SERINC proteins (Alli-Balogun and Levine, 2021).…”