TRIM7 restricts Coxsackievirus and norovirus infection by detecting the C-terminal glutamine generated by 3C protease processing

Abstract

TRIM7 catalyses the ubiquitination of multiple substrates with unrelated biological functions. This cross-reactivity is at odds with the specificity usually displayed by enzymes, including ubiquitin ligases. Here we show that TRIM7’s extreme substrate promiscuity is due to a highly unusual binding mechanism, in which the PRYSPRY domain captures any ligand with a C-terminal helix that terminates in a hydrophobic residue followed by a glutamine. Many of the non-structural proteins found in RNA viruses contain C-terminal glutamines as a result of polyprotein cleavage by 3C protease. This viral processing strategy generates novel substrates for TRIM7 and explains its ability to inhibit Coxsackie virus and norovirus replication. In addition to viral proteins, cellular proteins such as glycogenin have evolved C-termini that make them a TRIM7 substrate. The ‘helix-ΦQ’ degron motif recognised by TRIM7 is reminiscent of the N-end degron system and is found in ∼ 1% of cellular proteins. These features, together with TRIM7’s restricted tissue expression and lack of immune regulation suggest that viral restriction may not be its physiological function.

Interplay between TRIM7 and antiviral immunity

“…Additionally, TRIM7 also demonstrates inhibitory activity against non-human primate enteroviruses such as EV-B112, EV-B113, and EV-B114. (Fan et al, 2021;Liang et al, 2022;Luptak et al, 2022) Proviral role of TRIM7 TRIM7 mediates K63-linked ubiquitination of the ZIKV envelope protein, playing a critical role in determining the tissue tropism of ZIKV replication in vivo. (Giraldo et al, 2020) Enterovirus evasion strategies for antiviral role of TRIM7…”

“…Furthermore, TRIM7 has been identified as a negative regulator of STING expression. Echovirus11, PV, and NoVs, as well as non-human primate enteroviruses EV-B112, EV-B113, and EV-B114, by recognizing and targeting their C-terminal helix-FQ motif-containing (Fan et al, 2021;Luptak et al, 2022). However, TRIM7 does not exhibit inhibitory effects on other viruses, such as mouse enterovirus (MenV), yellow fever virus (YFV), Zika virus (ZIKV), and respiratory syncytial virus (RSV).…”

“…TRIM7 has also been found to recognize and interact with proteins or peptides containing the C-terminal helix-FQ motif, which includes proteins ending with either "LQ" or "FQ" (Luptak et al, 2022). This recognition mechanism is based on the observation that many viral genomes encode their major replicase components as single polypeptides that are subsequently processed into individual proteins by viral 3C proteases, which cleave after Q residues.…”