TY  - JOUR
AU  - Chen, Yuexuan
AU  - Klute, Susanne
AU  - Sparrer, Konstantin Maria Johannes
AU  - Serra-Moreno, Ruth
TI  - RAB5 is a host dependency factor for the generation of SARS-CoV-2 replication organelles.
JO  - mBio
VL  - 16
IS  - 5
SN  - 2161-2129
CY  - Washington, DC
PB  - American Society for Microbiology
M1  - DZNE-2025-00614
SP  - e0331424
PY  - 2025
AB  - 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.
KW  - Humans
KW  - rab5 GTP-Binding Proteins: metabolism
KW  - rab5 GTP-Binding Proteins: genetics
KW  - Virus Replication
KW  - SARS-CoV-2: physiology
KW  - SARS-CoV-2: genetics
KW  - Animals
KW  - COVID-19: virology
KW  - Host-Pathogen Interactions
KW  - Vero Cells
KW  - Chlorocebus aethiops
KW  - Viral Replication Compartments: metabolism
KW  - COP-I (Other)
KW  - COPB1 (Other)
KW  - NSP6 (Other)
KW  - RAB5 (Other)
KW  - SARS-CoV-2 (Other)
KW  - replication organelle (Other)
KW  - rab5 GTP-Binding Proteins (NLM Chemicals)
KW  - RAB5C protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40167317
C2  - pmc:PMC12077180
DO  - DOI:10.1128/mbio.03314-24
UR  - https://pub.dzne.de/record/278658
ER  -