Differential gene expression by RNA-Seq in Sigma-2 Receptor/TMEM97 knockout cells reveals its role in complement activation and SARS-CoV-2 viral uptake

Abstract

Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (sigma- 2R/TMEM97) interacts with the low-density lipoprotein receptor (LDLR) and facilitates the enhanced uptake of various ligands including lipoproteins and intrinsically disordered proteins. TMEM97 has been recently been shown to interact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins, highlighting its potential involvement with viral entry into the cell. We hypothesized that sigma-2R/TMEM97 may play a role in facilitating viral uptake, and with the regulation of inflammatory and thrombotic pathways that are involved with viral infection. In this study, we identified the top differentially expressed genes upon the knockout of sigma-2R/TMEM97, and analyzed the genes involved with the inflammatory and thrombotic cascades, effects that are observed in patients infected with SARS-CoV-2. We found that the ablation of sigma-2R/TMEM97 resulted in an increase in Complement Component 4 Binding Protein (C4BP) proteins, at both the translational and transcriptional levels. We also showed that sigma-2R/TMEM97 interacts with the cellular receptor for SARS-CoV-2, the human angiotensin-converting enzyme 2 (ACE2) receptor, forming a protein complex, and that disruption of this complex results in the inhibition of viral uptake. The results of this study suggest that sigma-2R/TMEM97 may be a novel therapeutic target to inhibit SARS- CoV-2 viral uptake, as well as to decrease inflammatory and thrombotic effects through the modulation of the complement cascade.

Computational Methods to Study Human Transcript Variants in COVID-19 Infected Lung Cancer Cells

“…The literature survey shows that three genes ( ANXA2 , CAV1 , and TMEM97 ) with the UTR-APA events related to SARS-CoV-2 pathogenesis and prognosis ( Table 3 ). For example, TMEM97 has been recently shown to interact with SARS-CoV-2 viral proteins [ 20 ].…”

“…CAV1 [19] Coronaviruses enter cells via the CAV1 dependent pathway. TMEM97 [20] TMEM97 forms a complex with ACE2 and modulates its ability to internalize the SARS-CoV-2.…”

“…The literature survey shows that three genes (ANXA2, CAV1, and TMEM97) with the UTR-APA events related to SARS-CoV-2 pathogenesis and prognosis (Table 3). For example, TMEM97 has been recently shown to interact with SARS-CoV-2 viral proteins [20]. In the CR-APA analysis, both the hg38 RefSeq annotation [28] and the UCSC annotation [29] were applied to report the list of CR-APA events between mock-treated versus SARS-CoV-2 infected cells.…”

Anaesthesia drugs, SARS-CoV-2, and the sigma-1 receptor: a complex affair. Comment on Br J Anaesth 2021; 127: e32–4

“…In a recent pre-print, Sig-2R was identified as a binding protein for SARS-CoV-2 viral protein Orf9c, and this interaction was found to increase Sig-2R/ACE2 complex formation and promote SARS-CoV-2 cell entry. 17 In the same study, Sig-2R ablation inhibited SARS-CoV-2 viral uptake, and decreased inflammatory and thrombotic effects in the modulation of the complement cascade.…”

“…As COVID-19 is a multisystem disorder with hyper-pro-inflammatory pathophysiology, 14 anaesthesia drugs such as dexmedetomidine that possess anti-inflammatory, cytoprotective, and organoprotective effects may be beneficial in COVID-19. 15 Apart from angiotensin converting enzyme 2 (ACE2) and Sig-1R, SARS-CoV-2 utilises other binding sites such as neuropilin-1 (NRP-1) 16 and sigma-2 receptor (Sig-2R) 17 for infecting host cells that may have limited association with anaesthesia drugs.…”