The authors were interested in TRIM5, a RING domain E3 ubiquitin ligase that has potent antiretroviral functions. Previous studies have found that TRIM5 assembles into a hexagonal lattice on retroviral capsids, leading to envelopment of the infectious core. At the same time, TRIM5 also initiates innate immune signalling, leading in turn to disassembly of the viral particle. The authors found that this hexagonal assembly triggers N-terminal polyubiquitination of TRIM5 that drives these antiviral responses. In uninfected cells, N-terminal monoubiquitination triggers non-productive TRIM5 turnover. When TRIM5 assembly occurred on the virus, a trivalent RING arrangement led to elongation of the N-terminally anchored K63-linked ubiquitin chains (N-K63-Ub). N-K63-Ub then drives TRIM5 innate immune stimulation and proteasomal degradation. If ubiquitination was induced before TRIM5 assembly then this triggers premature degradation and ablates the antiviral restriction. Conversely, driving N-K63 ubiquitination after TRIM5 assembly enhances innate immune signalling. Therefore the hexagonal geometry of TRIM5’s antiviral lattice converts a capsid-binding protein into a multifunctional antiviral platform.
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