TRIM5 is an innate immune sensor for the retrovirus capsid lattice

TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by HIV-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm1,2. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice3,4 and several reports indicate that TRIM5 plays a role in signal transduction5–7, but the precise mechanism of restriction is unknown8. Here we demonstrate that TRIM5 promotes innate immune signaling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13/UEV1A, TRIM5 catalyzes the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (MAP3K7) kinase complex and stimulate AP-1 and NFκB signaling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13/UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NFκB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13/UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signaling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.