Key result
SARS-CoV-2 nsp3 and nsp4 expression drives replication organelle biogenesis and forms double-membrane replicopores.
Why the study?
The exact components and structure of the SARS-CoV-2 double-membrane vesicle spanning pore remain to be determined.
SARS-CoV-2 nsp3 and nsp4 drive the biogenesis of replication organelles and form DMV-spanning replicopores, providing structural insights for potential antiviral targets.
May guide antiviral design targeting replication organelles; hypothesis-generating and requires validation before any clinical consideration.
Coronavirus replication is associated with the remodeling of cellular membranes resulting in the formation of double-membrane vesicles (DMVs). Recently, a pore spanning DMV was identified as a putative portal for viral RNA transcription and replication products providing a novel target for antiviral intervention. However, the exact components and the structure of the SARS-CoV-2 pore remain to be determined. Here, we investigate the structure of DMV pores by in situ cryo-electron tomography combined with subtomogram averaging. We reveal non-structural proteins (nsp) 3 and 4 as minimal components forming a DMV spanning pore and show that nsp3 Ubl1-Ubl2 domains are critical for inducing membrane curvature and DMV formation. Altogether, SARS-CoV-2 nsp3-4 has a dual role by driving the biogenesis of replication organelles and forming DMV-spanning replicopores. One-Sentence Summary Biogenesis of SARS-CoV-2 replication organelles is driven by nsp3-4 constituting the double-membrane vesicle spanning pore.
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Zimmermann et al. (2022) studied SARS-CoV-2. SARS-CoV-2 nsp3-4 expression vs. Untransfected cells or truncated nsp3-4 constructs was evaluated on Formation of double-membrane vesicles (DMVs) and DMV-spanning pores. Expression of SARS-CoV-2 non-structural proteins 3 and 4 is sufficient to drive the biogenesis of replication organelles and form double-membrane vesicle-spanning replicopores.
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