Interferon-induced transmembrane proteins (IFITMs) are antiviral factors that act uniquely and early in viral replication cycles to restrict the entry of a diverse range of primarily enveloped viruses into cells (1). Humans possess three IFN-inducible IFITM genes—IFITM1, IFITM2, and IFITM3—encoding proteins with antiviral functions and two IFITM family members that lack antiviral function—IFITM5 and IFITM10. Mice have orthologs of all these IFITMs as well as two additional genes, Ifitm6 and Ifitm7. Phylogenetic analysis of vertebrate IFITMs indicates that IFITM1, IFITM2, and IFITM3 group with murine ifitm6 and ifitm7 in a clade of immunity-related IFITMs (IR-IFITMs), with IFITM5 and IFITM10 falling as separate lineages (2). IFITMs belong to the CD225/pfam04505 or “dispanin” protein superfamily ( (3) that contains more than 2,000 members, including both prokaryotic and eukaryotic proteins, all of which encode a conserved CD225 protein domain.

..The subcellular localization of IFITMs is a key determinant of their antiviral profile. When expressed singly, IFITM3 and IFITM2 preferentially localize to early and late endosomes and lysosomes, restricting viruses that enter via these endolysosomal compartments. In contrast, IFITM1 primarily localizes at the cell surface and can restrict viruses that enter through the plasma membrane (11, 12, 13, 14). Indeed, mutants of IFITM3 that lack an N-terminal endocytic sorting motif 20YEML23 localize to the plasma membrane and lose their ability to inhibit influenza A virus (IAV), alphavirus, and coronavirus infection by endosomal routes (14, 15, 16, 17, 18).


IFITMs are heavily regulated by posttranslational modifications (PTMs). One major modification is S-palmitoylation, a reversible 16-carbon lipid PTM that increases protein hydrophobicity and influences the behavior of proteins in membrane environments (26). For human and murine IFITM3, S-palmitoylation can occur on cysteine residues 71, 72, and 105 and enhances IFITM3 antiviral activity (27, 28). Recent live-cell imaging showed that abrogating C72 palmitoylation slowed IFITM3 trafficking to membrane compartments containing IAV particles (20). Multiple zinc finger DHHC (Asp-His-His-Cys) domain–containing palmitoyltransferases (ZDHHCs) can palmitoylate IFITM3 with marked functional redundancy, although ZDHHC20 may be particularly important (29). For human IFITM3, C72 is also the dominant site for acylation (30). Three other PTMs have also been reported, all of which negatively regulate IFITM3 antiviral activity: ubiquitination on one or more of four lysine residues (27), methylation on K88 (31), and phosphorylation on Y20 (15, 16). IFITM3 also forms homo- and hetero-oligomers. Although these are thought to require amino acids F75 and F78 (22), a recent study reported that these residues are required for antiviral activity but not for IFITM3-IFITM3 interactions (32).


The antiviral responses of bats (mammalian order Chiroptera) are of particular interest because these animals have been increasingly recognized as reservoir hosts from which numerous viruses have ultimately emerged, with severe pathogenic and socioeconomic consequences in humans and livestock. Indeed, a recent analysis showed that bats host a significantly higher proportion of zoonotic viruses than other mammalian orders (47). Moreover, Chiroptera are the only mammalian order that harbor significantly more zoonotic viruses than predicted from reporting effort and host traits such as geographic range and mammal sympatry. It is possible that this propensity to be reservoirs for a large number of viruses, many of which may remain asymptomatic, in part reflects aspects of bat immunology (48, 49, 50, 51, 52). Hence, the study of Chiropteran antiviral effectors, such as IFITMs, can potentially reveal mechanisms of viral tolerance as well as the evolutionary signatures of virus–host co-evolution. We previously showed that microbat IFITM3 retains sequence motifs for endocytosis and PTM, traffics to the plasma membrane before endocytic uptake, co-localizes with endosomal markers, and at normal expression levels in primary microbat cells, inhibits infection by pH-dependent enveloped viruses (39).

Here, we performed evolutionary analyses of mammalian IFITMs, including those identified from bats, to shed light on IFITM function and the nature of past selection pressures, and to identify key amino acids for experimental studies of IFITM function.


To interferons!

March 1, 2020


The interferon-inducible transmembrane (IFITM) proteins 1, 2 and 3 inhibit the host cell entry of several enveloped viruses, potentially by promoting the accumulation of cholesterol in endosomal compartments. IFITM3 is essential for control of influenza virus infection in mice and humans.

In contrast, the role of IFITM proteins in coronavirus infection is less well defined. Employing a retroviral vector system for analysis of coronavirus entry, we investigated the susceptibility of human-adapted and emerging coronaviruses to inhibition by IFITM proteins. We found that entry of the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is sensitive to inhibition by IFITM proteins. In 293T cells, IFITM-mediated inhibition of cellular entry of the emerging MERS– and SARS-CoV was less efficient than blockade of entry of the globally circulating human coronaviruses 229E and NL63. Similar differences were not observed in A549 cells, suggesting that cellular context and/or IFITM expression levels can impact inhibition efficiency. The differential IFITM-sensitivity of coronaviruses observed in 293T cells afforded the opportunity to investigate whether efficiency of entry inhibition by IFITMs and endosomal cholesterol accumulation correlate. No such correlation was observed. Furthermore, entry mediated by the influenza virus hemagglutinin was robustly inhibited by IFITM3 but was insensitive to accumulation of endosomal cholesterol, indicating that modulation of cholesterol synthesis/transport did not account for the antiviral activity of IFITM3.

Collectively, these results show that the emerging MERS-CoV is a target of the antiviral activity of IFITM proteins and demonstrate that mechanisms other than accumulation of endosomal cholesterol can contribute to viral entry inhibition by IFITMs.

Keywords: IFITM, coronavirus, MERS, SARS


The implication of the renin-angiotensin system (RAS) in the regulation of the cardiovascular system has been well known for many years. Accordingly, many pharmaceutical inhibitors have been developed to treat several pathologies, like hypertension and heart failure, and angiotensin converting enzyme (ACE) became one of the major target in the treatment of these cardiovascular diseases. In the last decade however, it has become apparent that the classical view of the RAS was not quite accurate. For instance, ACE has been shown to work not only by generating angiotensin-II but also by interacting with receptors outside the renin-angiotensin system. (My comment: Kininogen- Kallikrein- Bradykinin/kallidin – receptors B1 and B2- signalling way ) Moreover, it has been shown that many local RAS are present in different tissues, such as the heart, brain, kidney and vasculature. However, in the past, it was impossible to determine the role of these local systems as they were pharmacologically indistinguishable from the systemic RAS. Hence, in recent years, the development of transgenic animals has allowed us to determine that these local systems are implicated in the roles that had been originally attributed exclusively to the systemic action of the RAS. However, with almost 30% of the medicated hypertensive patients harboring an uncontrolled blood pressure, a need for new drugs and new targets appears necessary. With the new century came the discovery of a new homolog of ACE, called ACE2, and early studies suggest that it may play a pivotal role in the RAS by controlling the balance between the vasoconstrictor effects of angiotensin- II and the vasodilatory properties of the angiotensin1-7 peptide. Like ACE, ACE2 appears to hydrolyze peptides not related with the RAS   and the enzyme has also been identified as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Although the tissue localization of ACE2 was originally though to be very restricted, new studies have emerged showing a more widespread distribution. Therefore, the whole dynamics of the RAS has to be re-evaluated in light of this new information. In this review, we will compare the structures, distributions and properties of ACE and its new homologue in the context of cardiovascular function, focusing on the autocrine/paracrine cardiac and brain renin-angiotensin systems and we will present recent data from the literature and our laboratory offering a new perspective on this potential target for the treatment of cardiovascular diseases. (My comment:  ACE and NEP hydrolyzes bradykinin and  kallidin ).

Keywords: ACE Polymorphism, membrane-bound ACE2 protein, Severe Acute Respiratory Syndrome, Heart failure, Hypertension

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