Coxsackievirus B3 Cleaves INTS10 Through 3C Protease to Facilitate Its Replication

Coxsackieviruses possess two proteases that are engaged in cleaving viral polyprotein and hijacking host cell processes such as RNA biosynthesis. Integrator subunit 10 (INTS10), a subunit of the integrator complex, facilitates the processing of small nuclear RNAs (U1 and U2 snRNAs) to regulate cellular transcription. We found that INST10 can be cleaved by Coxsackievirus B (CVB). Hence, we hypothesized that INST10 may play a role in CVB infection. In this study, INTS10 is identified as the substrate of CVB3 protease 3C (3C^pro). The cleavage occurs at the residue Q221 and yields a fragment. Depletion of INTS10 enhanced CVB3 replication and blocked snRNA processing. Overexpression of U1 snRNA inhibited CVB3 infection, whereas its knockdown conversely enhanced it. Similarly, knockdown of U2 snRNA was found to promote CVB3 replication. Taken together, the 3C^pro-mediated cleavage of INTS10 disrupts U snRNA processing, which in turn counteracts the inhibitory effect of snRNA U1 and U2 on virus replication and subverts host defenses.