Interferon‐inducible phospholipids govern IFITM3‐dependent endosomal antiviral immunity

Abstract

The interferon‐induced transmembrane proteins (IFITM) are implicated in several biological processes, including antiviral defense, but their modes of action remain debated. Here, taking advantage of pseudotyped viral entry assays and replicating viruses, we uncover the requirement of host co‐factors for endosomal antiviral inhibition through high‐throughput proteomics and lipidomics in cellular models of IFITM restriction. Unlike plasma membrane (PM)‐localized IFITM restriction that targets infectious SARS‐CoV2 and other PM‐fusing viral envelopes, inhibition of endosomal viral entry depends on lysines within the conserved IFITM intracellular loop. These residues recruit Phosphatidylinositol 3,4,5‐trisphosphate (PIP3) that we show here to be required for endosomal IFITM activity. We identify PIP3 as an interferon‐inducible phospholipid that acts as a rheostat for endosomal antiviral immunity. PIP3 levels correlated with the potency of endosomal IFITM restriction and exogenous PIP3 enhanced inhibition of endocytic viruses, including the recent SARS‐CoV2 Omicron variant. Together, our results identify PIP3 as a critical regulator of endosomal IFITM restriction linking it to the Pi3K/Akt/mTORC pathway and elucidate cell‐compartment‐specific antiviral mechanisms with potential relevance for the development of broadly acting antiviral strategies.

Red Blood Cells from Individuals with Lesch–Nyhan Syndrome: Multi-Omics Insights into a Novel S162N Mutation Causing Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency

“…Of note, kynurenine levels were elevated in the sibling not on allopurinol, which is relevant in that this tryptophan metabolite is elevated in response to cGAS-STING-interferon activation secondary to infections (e.g., SARS-CoV-2). Kynurenine catabolism has been linked to adverse neurological manifestations in other populations with genetic anomalies, like subjects suffering from Trisomy 21 [ 28 ] or Aicardi–Goutieres syndrome [ 29 ].…”

“…Interestingly, elevated kynurenine in Trisomy 21 is associated with the accumulation of its neurotoxicant catabolites [ 28 ], another phenotypic overlap between the LN patients investigated here and Down syndrome. In this view, it is worth noting that the activation of the interferon-indole 2,3-dioxygenase (IDO)-kynurenine axis is common among LN, Down syndrome, and Aicardi–Goutieres syndrome, also associated with clinical neurological manifestations [ 29 , 47 ]. Similarly, the elevated synthesis of neurotoxic kynurenine metabolites is a feature of glutaric aciduria type 1 (GA1).…”

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation

“…Indeed, IFITM3 silencing or inhibition ameliorates in vitro and in vivo phenotypes caused by CD151 removal. Notably, IFITM3 function in MVB requires its interaction with PIP3 through its intact, cytosol-facing lysine residues, 52 while excessive ubiquitination of IFITM3, as seen in CD151-removed cells, may impede and block this interaction and thereby compromise IFITM3 function. As pathophysiological functions of IFITM3 are expanded from earlier established preventive roles in the infection of enveloped viruses to newly discovered promotive roles in Alzheimer disease and B-cell leukemia, 12,18,53 our finding of CD151 as a crucial partner for IFITM3 prompts future studies on the link of CD151 to these diseases.…”

The Antiviral Activity of Interferon-Induced Transmembrane Proteins and Virus Evasion Strategies

“…IFITMs have also been shown to bind cholesterol via S-palmitoylation, and the antiviral activity of IFITMs is correlated with the level of S-palmitoylation [79]. IFITM3 recruits phosphatidylinositol 3,4,5-triphosphate (PIP3) via the lysine residues in the CIL domain [97,98] (Figure 4). These lysine residues are required for IFITM3 restriction of viral entry in endosomes not at the plasma membrane [97].…”

“…IFITM3 recruits phosphatidylinositol 3,4,5-triphosphate (PIP3) via the lysine residues in the CIL domain [97,98] (Figure 4). These lysine residues are required for IFITM3 restriction of viral entry in endosomes not at the plasma membrane [97]. Continuum modeling of the IAV-endosome fusion site The IFITM-mediated modulation of membrane fluidity and curvature may be attributed to its ability to undergo lipid sorting [16,91,96].…”