SARS-CoV-2 nsp14 induces the m7G methylation and the sequestration of host RNAs in stress granules.

Viruses hijack the host translation machinery to facilitate their replication by disturbing the host translation. SARS-CoV-2 nsp14 is known to inhibit host translation, yet the mechanistic details are still obscure. In this study, we report that nsp14 can elevate stress granules (SG) formation in a N7-methyltransferase activity-dependent manner. ER/Golgi localized nsp14 promotes m7G methylation of host RNAs, which are delivered into stress granules (SG), leading to elevated SG formation. Except for a few methylation-associated proteins, most components of SGs induced by nsp14 can be identified in SGs induced by other stress inducers, like sodium arsenite. Nsp14-induced SG formation relies on methyl donors, because altering the amount of methyl donors, like decreasing SAM level with overexpression of Glycine N-methyltransferase (GNMT) or increasing SAM level with the supplement of folic acid, can alter SG formation and affect viral replication. Collectively, we characterize nsp14 as an SG formation regulator involved in viral hijacking of the host translation machinery.