The human LRRC15 protein is an inhibitory receptor for SARS-CoV-2 spike-mediated entry.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China in late December 2019, and subsequently caused a pandemic of coronavirus disease 2019 (COVID-19).

SARS-CoV-2 infection is promoted by the entry receptor angiotensin converting enzyme 2 (ACE2). Adhesive factors and co-receptors that promote invasion have been extensively studied. However, little is known about cell entry factors that block viral entry.

Recent studies have shown that bioRxiv* Preprint server, researchers have identified human LRRC15 as an inhibitory receptor for SARS-CoV-2 invasion. this is, Spike protein It has a moderate affinity and suppresses invasion through spikes.

study: LRRC15 is an inhibitory receptor that blocks the entry of trans through the SARS-CoV-2 spike... Image Credit: DottedYeti / Shutterstock

Background and motive

Like SARS-CoV-1, SARS-CoV-2 utilizes ACE2 as the major enteric receptor. Viral structure protein spike (S) binds to ACE2 and mediates viral cell invasion. The S1 subunit is composed of the N-terminal domain (NTD) and the receptor binding domain (RBD).

The interaction between RBD and ACE2 is important in determining some important features of SARS-CoV-2 infection.Peplomers (especially RBD) are the main targets antigen For COVID-19 vaccines that block binding between RBD and ACE2. This highlights the importance of binding RBD and its cell receptors to regulate SARS-CoV-2.

Scientists have identified several cellular factors that promote SARS-CoV-2 cell entry, but it is not clear whether cell receptors block viral entry. In the current study, researchers have generated a focused CRISPRa library named surfaceome. The library covers approximately 6,000 of all known / predicted surface proteins on the plasma membrane.

The screening method used revealed that human LRRC15 (leucine-rich repeat-containing 15) is a novel inhibitory receptor for SARS-CoV-2.

Main survey results

Scientists sought to identify the cellular receptor for SARS-CoV-2 by staining cells with recombinant peplomer. This resulted in two different hits, ACE2 and LRRC15. Of course, ACE2 is a bonafido entry receptor and LRRC15 is a novel inhibitory receptor. In addition, LRRC15 was observed to interact directly with S’s RBD with moderate affinity.

Previous studies have shown that ACE2 also interacts with S (via RBD), but the LRRC15-RBD interaction does not compete with or stabilize the ACE2-RBD interaction. There was no. However, higher resolution research is required to determine the interface of the LRRC15-RBD.

A notable observation was that in addition to the same cells, LRRC15 also inhibited viral entry into adjacent cells. In a transformer..

By interacting with the peplomer itself, inhibition of viral entry by LRRC15 showed a direct effector. Often, the LRR domain is associated with the detection of pathogen-associated molecular patterns (PAMPs).

One of the notable features of LRR domain proteins is that they are highly conserved (even in plants). This provides excellent protection against pathogens.

Humans may develop certain types of pattern recognition proteins coronavirusGiven the role of the LRR domain in pattern recognition.

The inhibitory effect of LRRC15 on coronavirus means an arms race between humans and coronavirus. In addition, during the preparation of the manuscript for the current study, LRRC15 was identified as a SARS-CoV-2 spike-binding factor in two other studies, demonstrating the robust and detectable properties of the LRRC15-spike interaction.

Many interferon-stimulating genes (ISGs) such as LY6E, CH25H, and IFITM have been shown to prevent coronavirus invasion by interfering with peplomer-mediated membrane fusion.

Alternatively, ISG can also interfere with endosome-mediated processes. However, the mechanism of action of ISG and LRRC15 is completely different.

LRRC15 is not induced by interferon and its inhibitory effects are directly mediated by interaction with spikes that resemble PAMP receptors.

Scientists have stated that LRRC15 can act as an antiviral factor via a variety of modes, as it redistributes adenovirus receptors and thereby affects the delivery of adenovirus to cells. rice field.

Future studies will need to determine whether LRRC15 requires intracellular signaling (via the cytosol domain) or other cellular proteins for inhibition.

Researchers Trance-Virus suppression is noteworthy. They co-cultured ACE2 + LRRC15- cells and ACE2-LRRC15 + cells and observed significant suppression of viral infection. This indicates that the antiviral effect of LRRC15 can be widespread in physiological situations. In the human lung, LRRC15 acts as an entry inhibitor and may act as a virus control during SARS-CoV-2 infection.

Conclusion

Adhesive factors and co-receptors that promote SARS-CoV-2 invasion have been extensively studied, but few are known to inhibit viral invasion.

Current studies have shown that LRRC15 (by interacting directly with the spike protein) is a receptor for SARS-CoV-2 spikes and exhibits inhibition such as pattern recognition of viral entry.

Therefore, this study provided new insights for the development of treatments and a better understanding of COVID-19.

*Important Notices

bioRxiv Publish preliminary scientific reports that should not be considered definitive as they have not been peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.