Human Helicase DDX5 is Hijacked by SARS-CoV‑2 Nsp13 Helicase to Enhance RNA Unwinding

TL;DR

The study reveals that the human protein DDX5 interacts with SARS-CoV-2's Nsp13 helicase to enhance RNA unwinding, a key step in viral replication.

Contribution

The paper identifies a novel synergistic interaction between DDX5 and SARS-CoV-2 Nsp13 helicase that enhances RNA unwinding.

Findings

DDX5 binds to SARS-CoV-2 Nsp13 helicase with nanomolar affinity.

The RecA1 domain of DDX5 mediates the interaction with Nsp13 and weakly inhibits their synergistic RNA unwinding.

DDX5 and Nsp13 work together to unwind RNA, likely aiding early stages of SARS-CoV-2 infection.

Abstract

DEAD-box protein (DDX) 5 plays important roles in multiple
aspects
of cellular processes that require modulation of the RNA structure.
Alongside the canonical role in RNA metabolism, numerous studies have
demonstrated that DDX5 influences viral infections by directly interacting
with viral proteins. However, the precise functional role of DDX5
during viral infection remains largely unclear. Here, we explore the
previously undiscovered ability of DDX5 to interact and synergize
with the Nsp13 helicase of SARS-CoV-2. We show that DDX5 exhibits
a nanomolar binding affinity to Nsp13. Also, by dissecting DDX5 in
its individual domains, we show that the Nsp13–DDX5 interaction
is mediated by the RecA1 domain of DDX5. Importantly, we show that
DDX5 and Nsp13 synergize in unwinding double-stranded RNA. Consistent
with its ability to bind Nsp13, the RecA1 domain of DDX5 acts as a
weak inhibitor of the synergic action of the two helicases in the
RNA unwinding process. Modeling of the DDX5–Nsp13 complex provides
a plausible explanation for the synergic action of the two helicases,
in a mechanism that is likely instrumental in the early stage of infection,
when the concentration of Nsp13 is still low.

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