Journal Article

DZNE-2025-00614

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png RAB5 is a host dependency factor for the generation of SARS-CoV-2 replication organelles.

Chen, Y. ; Klute, S.Extern* ; Sparrer, K. M. J.DZNE* ; Serra-Moreno, R.

2025
American Society for Microbiology Washington, DC

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Please use a persistent id in citations: doi:10.1128/mbio.03314-24

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a threat due to the emergence of variants with increased transmissibility and enhanced escape from immune responses. Like other coronaviruses before, SARS-CoV-2 likely emerged after its transmission from bats. The successful propagation of SARS-CoV-2 in humans might have been facilitated by usurping evolutionarily conserved cellular factors to execute crucial steps in its life cycle, such as the generation of replication organelles-membrane structures where coronaviruses assemble their replication-transcription complex. In this study, we found that RAB5, which is highly conserved across mammals, is a critical host dependency factor for the replication of the SARS-CoV-2 genome. Our results also suggest that SARS-CoV-2 uses RAB5+ membranes to build replication organelles with the aid of COPB1, a component of the COP-I complex, and that the virus protein NSP6 participates in this process. Hence, targeting NSP6 represents a promising approach to interfere with SARS-CoV-2 RNA synthesis and halt its propagation.IMPORTANCEIn this study, we sought to identify the host dependency factors that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses for the generation of replication organelles: cellular membranous structures that SARS-CoV-2 builds in order to support the replication and transcription of its genome. We uncovered that RAB5 is an important dependency factor for SARS-CoV-2 replication and the generation of replication organelles, and that the viral protein NSP6 participates in this process. Hence, NSP6 represents a promising target to halt SARS-CoV-2 replication.

Keyword(s): Humans (MeSH) ; rab5 GTP-Binding Proteins: metabolism (MeSH) ; rab5 GTP-Binding Proteins: genetics (MeSH) ; Virus Replication (MeSH) ; SARS-CoV-2: physiology (MeSH) ; SARS-CoV-2: genetics (MeSH) ; Animals (MeSH) ; COVID-19: virology (MeSH) ; Host-Pathogen Interactions (MeSH) ; Vero Cells (MeSH) ; Chlorocebus aethiops (MeSH) ; Viral Replication Compartments: metabolism (MeSH) ; COP-I ; COPB1 ; NSP6 ; RAB5 ; SARS-CoV-2 ; replication organelle ; rab5 GTP-Binding Proteins ; RAB5C protein, human

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Contributing Institute(s):

1. Neurovirology and Neuroinflammation (AG Sparrer)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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