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Background and Aims  Hepatitis E virus (HEV) is one of the most common causes of acute hepatitis worldwide. Its positive‐strand RNA genome encodes three open reading frames (ORF). ORF1 is translated into a large protein composed of multiple domains and is known as the viral replicase. The RNA‐dependent RNA polymerase (RDRP) domain is responsible for the synthesis of viral RNA.    Approach and Results  Here, we identified a highly conserved α‐helix located in the RDRP thumb subdomain. Nuclear magnetic resonance demonstrated an amphipathic α‐helix extending from amino acids 1628 to 1644 of the ORF1 protein. Functional analyses revealed a dual role of this helix in HEV RNA replication and virus production, including assembly and release. Mutations on the hydrophobic side of the amphipathic α‐helix impaired RNA replication and resulted in the selection of a second‐site compensatory change in the RDRP palm subdomain. Other mutations enhanced RNA replication but impaired virus assembly and/or release.    Conclusions  Structure‐function analyses identified a conserved amphipathic α‐helix in the thumb subdomain of the HEV RDRP with a dual role in viral RNA replication and infectious particle production. This study provides structural insights into a key segment of the ORF1 protein and describes the successful use of reverse genetics in HEV, revealing functional interactions between the RDRP thumb and palm subdomains. On a broader scale, it demonstrates that the HEV replicase, similar to those of other positive‐strand RNA viruses, is also involved in virus production.

Hepatitis E virus RNA‐dependent RNA polymerase is involved in RNA replication and infectious particle production