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Distinct RNA engagements define genome import and replication elongation in alphaviruses

Tan, Y. B.; Luo, Y.; Liu, P.; Merits, A.; Luo, D.

2026-07-03 microbiology
10.64898/2026.07.03.736289 bioRxiv
Show abstract

Membrane-associated replication complexes (RCs) are a hallmark of alphaviruses, yet the mechanisms by which viral RNA is delivered into these compartments and coordinated with RNA synthesis remain incompletely understood. Here, we present a cryo-electron microscopy (cryo-EM) structure of the Chikungunya virus (CHIKV) RC core, consisting of nsP1, nsP2, and nsP4, in complex with the replicative RNA substrates, revealing two spatially distinct RNA-binding sites. A single-stranded RNA (ssRNA) engages the nsP2 helicase and extends toward a pore formed at the nsP1-nsP4 interface, whereas a double-stranded RNA (dsRNA) is accommodated within the central catalytic pocket of the nsP4 polymerase in an elongation configuration. Structural analysis suggests a helicase-assisted RNA threading model in which the 5' end of the viral genome is guided toward the spherule lumen through the RC pore. Concurrently, the nsP4 polymerase engages dsRNA in a manner consistent with RNA synthesis. This work provides a structural framework for understanding RNA trafficking and enzymatic coordination in viral replication organelles.

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