Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.03.14.435180

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

Riad, A.·Aubert, Y.·Zeng, C.·Graham, T. J. A.·Petersson, E. J.·Capell, B. C.·Mach, R. H.
View original source ↗Export metadata ↓

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.

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Riad, A., Aubert, Y., Zeng, C., Graham, T. J. A., Petersson, E. J., Capell, B. C., Mach, R. H.. 2021-03-15. 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. https://doi.org/10.1101/2021.03.14.435180

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Sequential pathways preserve kinetochore integrity in meiosis

Kinetochores connect chromosomes to spindle microtubules, but how their integrity is maintained as they are remodelled during meiosis remains poorly understood. Here, we identify three distinct pathways linking centromeric chromatin to the outer kinetochore in budding yeast, mediated by the Ctf19 complex (Ctf19cCCAN), Mif2CENP-C and binding of Okp1CENP-Q-Ame1CENP-U to the Cse4CENP-A essential N-terminal domain (END). Although partially redundant during mitosis, all three connections are required during meiosis, with distinct temporal requirements. The assembled Ctf19cCCAN and Mif2CENP-C-dependent pathways maintain kinetochore integrity from meiotic entry, while Cse4CENP-A-Okp1CENP-Q-Ame1CENP-U binding becomes critical during prophase and the meiotic divisions. We further show that Ipl1Aurora B maintains kinetochore integrity independently of Ctf19cCCAN and provide evidence for an outer kinetochore-associated Ipl1Aurora B pool. Strikingly, Cse4CENP-A phosphomimetic mutations that restore kinetochore integrity upon Ipl1Aurora B depletion instead exacerbate defects in cells lacking Ctf19cCCAN. Our findings suggest that phosphorylation of the Cse4CENP-A N-terminal domain (NTD) by Ipl1Aurora B may regulate the use of alternative centromere-kinetochore connections to adapt to the changing requirements of meiosis.

cell biology↗
bioRxiv2026

Endothelial Cell Specific Thioredoxin 1-Dependent Signaling in Oxygen-1 Induced Retinopathy

Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness, characterized byoxidative stress and dysregulated angiogenesis in preterm infants with immature antioxidant systems.This study aimed to investigate the specific role of endothelial cell-specific thioredoxin 1 (TXN1), a crucial oxidoreductase, in oxygen-induced retinopathy, hypothesizing that the absence of endothelial TXN1 directly impairs angiogenesis and exacerbates hyperoxia-induced injury. Methods: We generated tamoxifen-inducible, endothelial cell-specific Txn1 knockout mice (Txn1-iECKO) and utilized the oxygen-induced retinopathy (OIR) model, exposing litters to 85% oxygen from postnatal day 7 (P7) to P12. Retinal vascular morphology during vaso-obliteration and neovascularization phases, endothelial cell proliferation, and apoptotic cell death were assessed. Furthermore, human retinal microvascular endothelial cells (HRMECs) with TXN1 knockdown were subjected to hyperoxic conditions, followed by comprehensive gene expression profiling using RT2 Profiler PCR arrays and Ingenuity Pathway Analysis. Results: Deletion of endothelial Txn1 significantly enhanced vascular regression during the hyperoxic vaso-obliteration phase at P12 and markedly exacerbated pathological neovascularization at P17. Txn1-deficient retinas exhibited significantly impaired endothelial cell proliferation during the vaso-obliteration phase, while apoptotic cell death remained unchanged. Transcriptomic analysis of TXN1-deficient HRMECs under hyperoxia revealed an enhanced activation of NRF2-mediated oxidative stress response pathways. Conclusions: These findings identify endothelial TXN1 as an essential and oxygen-dependent regulator of vascular development in ischemic retinopathy, primarily influencing endothelial proliferation and redox signaling. This suggests TXN1's crucial protective role and highlights its therapeutic potential to mitigate ROP progression by modulating endothelial cell responses to oxidative stress.

cell biology↗
bioRxiv2026

A Dynamic Stem Cell State Links Environmental Cues to Skeletal and Regenerative Fates

Stem cells faithfully generate tissue architecture during development, yet how their identity and regenerative output are reshaped as anatomical niches mature and environmental signals change with aging and injury remains poorly understood. Rare skeletal stem cells (SSCs) across diverse skeletal sites are defined by combinations of cell-surface markers, precluding their genetic interrogation in vivo. Here, using spatially informed single cell transcriptomics, we identify Pannexin-3 (Panx3) to mark a dynamic functional state within bona fide SSCs and establish Panx3-CreERT2 mice for its longitudinal interrogation. Panx3 SSCs exhibit long-term clonal persistence, self-renewal and multipotency, whereas Panx3- SSCs can acquire this state. Successive SSC cohorts engage the Panx3 state during skeletal development, osteoanabolic stimulation expands pre-existing Panx3 SSC clones and injury induces it locally in previously unlabeled progenitors. Thus, anatomically distinct progenitors can converge on a common stem cell state in response to different environmental inputs. Three-dimensional reconstruction of chondrogenic niches further identifies signals that redirect Panx3-lineage cells towards stable cartilage, enabling durable regeneration in aged and osteoarthritic joints and with human SSCs. These findings establish anatomical origin, stem cell state and lineage fate as separable dimensions of stem cell identity and provide genetic access for interrogating and directing endogenous SSC function.

cell biology↗