The role of the cellular proteasome and ubiquitin in post-entry restriction of retroviruses by TRIM5α

Abstract

The host protein TRIM5α inhibits retroviral infection at an early post-penetration stage by binding to the incoming viral capsid. Interaction with TRIM5α results in a failure of the virus to complete reverse transcription through an unknown mechanism. I have discovered that infection of cells with a restricted retrovirus leads to degradation of TRIM5α in the target cells. This degradation strongly correlates with restriction, is dose dependent, and inversely correlates with infection. Viral-induced degradation of TRIM5α is dependent on the presence of the RING domain of TRIM5α and a functional cellular proteasome. I have also found evidence linking the UbcH5 family of E2 ubiquitin conjugases to a role in post-entry restriction of HIV-1 by rhesus macaque-derived TRIM5α. These findings establish a connection between post-entry restriction by TRIM5α and the ubiquitin-proteasome pathway and indicate a mechanism of retroviral restriction by TRIM5α.