tetano
Editor, Senior Moderator
J Biol Chem
. 2025 Oct 13:110812.
doi: 10.1016/j.jbc.2025.110812. Online ahead of print. Long non-coding RNA enhances SARS-CoV-2-mediated apoptosis through epigenetic repression of angiotensin-converting enzyme 2
Weijie Liao[SUP] 1 [/SUP], Tian Zhang[SUP] 2 [/SUP], Jiaxing Cao[SUP] 3 [/SUP], Songmao Wang[SUP] 4 [/SUP], Yaou Zhang[SUP] 5 [/SUP]
Affiliations
Despite its critical role in organ protection, angiotensin-converting enzyme 2 (ACE2) is paradoxically downregulated during SARS-CoV-2 infection, contributing to multi-organ dysfunction in COVID-19. The mechanisms driving this loss, particularly those mediated by long non-coding RNAs (lncRNAs), are unknown. Through transcriptomic analysis, we identified that the lncRNA EPB41L4A-AS1 (EAS1) is consistently upregulated upon infection by multiple coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-229E. Mechanistically, SARS-CoV-2 infection activates HIF-1α, which binds to an enhancer element within the EAS1 locus to drive its expression. Subsequently, EAS1 recruits the acetyltransferase GCN5 to catalyze the acetylation of the transcriptional coactivator PGC1β. This modification disrupts the interaction between PGC1β and the transcription factor PPARγ, thereby impairing PPARγ-mediated transactivation of the ACE2 gene and leading to its transcriptional repression. Functionally, we demonstrate that this EAS1-mediated suppression of ACE2 exacerbates cellular apoptosis induced by TNF-α and hypoxia, two key pathological features of severe COVID-19. Our study unveils a novel epigenetic pathway through which SARS-CoV-2 dysregulates ACE2 expression and promotes cellular damage. Given the persistent threat of recurrent coronavirus spillovers, the conserved upregulation of EAS1 across distinct coronavirus genera suggests it may represent a potential therapeutic target for mitigating organ injury in COVID-19. Furthermore, our findings that the EAS1-ACE2 axis mediates apoptosis in response to hypoxia and cytokine signaling warrant future investigation into its role in other pathological contexts beyond viral infection.
Keywords: ACE2; Apoptosis; EPB41L4A-AS1; HIF-1α; SARS-CoV-2.
. 2025 Oct 13:110812.
doi: 10.1016/j.jbc.2025.110812. Online ahead of print. Long non-coding RNA enhances SARS-CoV-2-mediated apoptosis through epigenetic repression of angiotensin-converting enzyme 2
Weijie Liao[SUP] 1 [/SUP], Tian Zhang[SUP] 2 [/SUP], Jiaxing Cao[SUP] 3 [/SUP], Songmao Wang[SUP] 4 [/SUP], Yaou Zhang[SUP] 5 [/SUP]
Affiliations
- PMID: 41093073
- DOI: 10.1016/j.jbc.2025.110812
Despite its critical role in organ protection, angiotensin-converting enzyme 2 (ACE2) is paradoxically downregulated during SARS-CoV-2 infection, contributing to multi-organ dysfunction in COVID-19. The mechanisms driving this loss, particularly those mediated by long non-coding RNAs (lncRNAs), are unknown. Through transcriptomic analysis, we identified that the lncRNA EPB41L4A-AS1 (EAS1) is consistently upregulated upon infection by multiple coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-229E. Mechanistically, SARS-CoV-2 infection activates HIF-1α, which binds to an enhancer element within the EAS1 locus to drive its expression. Subsequently, EAS1 recruits the acetyltransferase GCN5 to catalyze the acetylation of the transcriptional coactivator PGC1β. This modification disrupts the interaction between PGC1β and the transcription factor PPARγ, thereby impairing PPARγ-mediated transactivation of the ACE2 gene and leading to its transcriptional repression. Functionally, we demonstrate that this EAS1-mediated suppression of ACE2 exacerbates cellular apoptosis induced by TNF-α and hypoxia, two key pathological features of severe COVID-19. Our study unveils a novel epigenetic pathway through which SARS-CoV-2 dysregulates ACE2 expression and promotes cellular damage. Given the persistent threat of recurrent coronavirus spillovers, the conserved upregulation of EAS1 across distinct coronavirus genera suggests it may represent a potential therapeutic target for mitigating organ injury in COVID-19. Furthermore, our findings that the EAS1-ACE2 axis mediates apoptosis in response to hypoxia and cytokine signaling warrant future investigation into its role in other pathological contexts beyond viral infection.
Keywords: ACE2; Apoptosis; EPB41L4A-AS1; HIF-1α; SARS-CoV-2.