SARS-CoV-2 ORF3a-Mediated NF-κB Activation Is Not Dependent on TRAF-Binding Sequence

Busscher, Brianna M.; Befekadu, Henock B.; Liu, Zhonghua; Xiao, Tsan Sam

doi:10.3390/v15112229

Cited by 2 publications

(2 citation statements)

References 50 publications

(102 reference statements)

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“…The ORF3a protein exhibits several well-conserved functional motifs (Figure 1A), allowing us to hypothesize about its potential functions. Notably, it contains a TNF receptor-associated factor 3 (TRAF3)-binding motif spanning aa36-40 in both SARS-CoV-1 and SARS-CoV-2 [37,38,47,55]. Interestingly, TRAF3 plays a crucial role in regulating NF-κB signaling and cell death in SARS-CoV-1.…”

Section: Structure and Unique Features Of Orf3a Proteinmentioning

confidence: 99%

“…Initial reports suggested that the interaction between ORF3a and TRAF3 through this binding site was necessary for the activation of NF-κB and the secretion of the cytokine IL-1β [37,38]. However, studies on SARS-CoV-2 indicated that deletion of this TRAF3-binding motif in the ORF3a protein did not affect its ability to induce NF-κB activation or NF-κB-mediated cytokine production [47,55]. The underlying cause of this discrepancy is presently unclear.…”

Section: Structure and Unique Features Of Orf3a Proteinmentioning

confidence: 99%

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SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects

Zhang,

Hom,

Zhang

et al. 2024

Pathogens

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The COVID-19 pandemic caused by SARS-CoV-2 has posed unparalleled challenges due to its rapid transmission, ability to mutate, high mortality and morbidity, and enduring health complications. Vaccines have exhibited effectiveness, but their efficacy diminishes over time while new variants continue to emerge. Antiviral medications offer a viable alternative, but their success has been inconsistent. Therefore, there remains an ongoing need to identify innovative antiviral drugs for treating COVID-19 and its post-infection complications. The ORF3a (open reading frame 3a) protein found in SARS-CoV-2, represents a promising target for antiviral treatment due to its multifaceted role in viral pathogenesis, cytokine storms, disease severity, and mortality. ORF3a contributes significantly to viral pathogenesis by facilitating viral assembly and release, essential processes in the viral life cycle, while also suppressing the body’s antiviral responses, thus aiding viral replication. ORF3a also has been implicated in triggering excessive inflammation, characterized by NF-κB-mediated cytokine production, ultimately leading to apoptotic cell death and tissue damage in the lungs, kidneys, and the central nervous system. Additionally, ORF3a triggers the activation of the NLRP3 inflammasome, inciting a cytokine storm, which is a major contributor to the severity of the disease and subsequent mortality. As with the spike protein, ORF3a also undergoes mutations, and certain mutant variants correlate with heightened disease severity in COVID-19. These mutations may influence viral replication and host cellular inflammatory responses. While establishing a direct link between ORF3a and mortality is difficult, its involvement in promoting inflammation and exacerbating disease severity likely contributes to higher mortality rates in severe COVID-19 cases. This review offers a comprehensive and detailed exploration of ORF3a’s potential as an innovative antiviral drug target. Additionally, we outline potential strategies for discovering and developing ORF3a inhibitor drugs to counteract its harmful effects, alleviate tissue damage, and reduce the severity of COVID-19 and its lingering complications.

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Section: Structure and Unique Features Of Orf3a Proteinmentioning

confidence: 99%

Section: Structure and Unique Features Of Orf3a Proteinmentioning

confidence: 99%

SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects

Zhang,

Hom,

Zhang

et al. 2024

Pathogens

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Highly ordered clustering of TNFα and BAFF ligand-receptor-adaptor complexes bound to lipid membranes

Lim,

Lee,

Kim

et al. 2024

Preprint

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We report the cryo-EM structures of clusters of TNF receptor family proteins, TNFR1 and BAFFR. The receptor-ligand complexes were anchored to a flat lipid layer to mimic the membrane-bound state. We observed that the TNFα-TNFR1 complex forms highly ordered binary, bent, trigonal, and linear quadruple clusters of trimers on the lipid membrane. A non-competitive antagonist of TNFR1 disrupted these clusters without interfering with ligand binding. Moreover, we found that the BAFF-BAFFR complex forms pentagonal, double-pentagonal, or half-spherical clusters of trimers. Mutations in BAFF that inhibit BAFFR receptor activation prevented ordered clustering without disrupting receptor binding. TRAF3 induced a structural shift in the BAFF-BAFFR cluster, resulting in a flat hexagonal cluster. Our data demonstrated that precisely structured clustering is essential for the activation of these receptors. The lipid monolayer method will aid in studying the clusters of other transmembrane proteins and facilitate the discovery of therapeutic agents that regulate their clustering.

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SARS-CoV-2 ORF3a-Mediated NF-κB Activation Is Not Dependent on TRAF-Binding Sequence

Cited by 2 publications

References 50 publications

SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects

SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects

Highly ordered clustering of TNFα and BAFF ligand-receptor-adaptor complexes bound to lipid membranes

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