SARS-CoV-2 linoleic acid binding sites in membrane navigation: sensing vs. scavenging

To the Editor: Toelzer and colleagues identified linoleic acid (LA) binding pockets in the SARS-CoV-2 protein, modulating its binding affinity to ACE2 (1). The purpose of this letter is to propose a model where LA binding serves as a sensing / scavenging mechanism that determines SARS-CoV-2’s (a) membrane polarity, via sensing (b) modulate non-ACE2 spike protein interactions via sensing/scavenging during its intracellular lifecycle. Examining the lipidomic profile of cells infected by HCoV-229E, LA upregulation was the result of membrane catabolism via the activation of cytocolic PLA2 (2). Notably, aside from a metabolite, LA functions as an endogenous inhibitor of PLA2 (3), indicating that its restriction (via SARS-CoV-2 sensing/scavenging) would disinhibit PLA2. Conversely, as shown in a murine model of SARS-CoV infection, PLA2 group IID (PLA2G2D) knockdown resulted in the increased (>80%) survival compared to wildtype (4). The cellular compartment sensing hypothesis is further supported by SARS-CoV-2 with NEDD4, an E3 ubiquitin ligase that controls ACE2 receptor cycling (5) and whose abundance is determined by LA levels (6). The interaction between NEDD4 and the recently PPXY motif in SARS-CoV-2’s Spike appears to be a conserved strategy in enveloped RNA viruses (7), with ubiquitylation of viral proteins by the hosts’ NEDD4 family enabling trafficking along the vesicular pathway. SARS-CoV-2 LA sequestration would result in subverting ACE2 cycling, limit NEDD4.2 abundance and subsequently exploit S PPxY-NEDD4 binding in order to facilitate egress. This proposed mechanism of lipid sensing would allow endocytosed SARS-CoV-2 to establish the membrane milieu in association with cytosolic PLA2 production of LA following membrane degradation. During egress, modifications on the RBD as proposed by Toelzen and colleagues could favor NEDD4 – Spike PPXY interactions, with LA sequestering buffering NEDD4 activity as appropriate (i.e. potentially reducing ACE2 ubiquitylation). Interestingly, LA sensing may also protect SARS-CoV-2 from inactivation by deleterious interactions with soluble ACE2 (8).