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A Key Viral Factor for COVID-19 Virulence: SARS-CoV-2 ORF7b Dysregulates the Lysosomal-Autophagy System for Enhanced Replication

ABSTRACT: The pandemic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is known for its high infectivity, high replication rate, and rapid transmission in humans. However, the key viral factor that determines these features has yet to be identified. In this study, the SARS-CoV-2 ORF7b protein was identified as a key factor promoting viral replication and infectivity, leading to the rapid spread of the virus to neighboring cells. Mechanistically, ORF7b blocks the assembly of the V0 complex of the v-type ATPase proton pump by hijacking and inducing the degradation of V0 complex subunits. This interference prevents the formation of the V0-V1 complex, resulting in lysosomal de-acidification. Furthermore, ORF7b promotes autophagy activation through the GCN2 pathway, which is linked to amino acid deprivation signaling. Pharmacological interventions demonstrated that lysosomal activation via ATPase agonists effectively inhibited viral spread, while inhibiting GCN2-dependent autophagy activation suppressed viral replication. In a mouse model, these pharmacological agents also reduced lung viral replication, inflammation, and mitigated lung damage. These novel findings demonstrate that ORF7b plays a pivotal role in the viral life cycle by dysregulating the host's lysosomal-autophagy system, positioning this host pathway as a potential therapeutic target for COVID-19 treatment.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Shin-Gu choul

PROVIDER: PXD069974 | JPOST Repository | Thu Apr 30 00:00:00 BST 2026

REPOSITORIES: jPOST

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			Action	DRS
	240331_C19_F01.pdResult	Other
	240331_C19_F01.raw	Raw
	240331_C19_F02.raw	Raw
	240331_C19_F03.raw	Raw
	240331_C19_F04.raw	Raw

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