TRIM E3 Ligases Interfere with Early and Late Stages of the Retroviral Life Cycle

Abstract

Members of the TRIpartite interaction Motif (TRIM) family of E3 ligases have been shown to exhibit antiviral activities. Here we report a near comprehensive screen for antiretroviral activities of 55 TRIM proteins (36 human, 19 mouse). We identified ∼20 TRIM proteins that, when transiently expressed in HEK293 cells, affect the entry or release of human immunodeficiency virus 1 (HIV), murine leukemia virus (MLV), or avian leukosis virus (ALV). While TRIM11 and 31 inhibited HIV entry, TRIM11 enhanced N-MLV entry by interfering with Ref1 restriction. Strikingly, many TRIM proteins affected late stages of the viral life cycle. Gene silencing of endogenously expressed TRIM 25, 31, and 62 inhibited viral release indicating that they play an important role at late stages of the viral life cycle. In contrast, downregulation of TRIM11 and 15 enhanced virus release suggesting that these proteins contribute to the endogenous restriction of retroviruses in cells.

Author Summary

A lot of excitement in the field of innate immunity to retroviruses such as HIV has come from the discovery of TRIM5 as a key player in cross species restriction. TRIM5 belongs to a family of E3 ligases with over 70 members, a number of which have exhibited antiviral activity. These findings have led to the hypothesis that several TRIM proteins may contribute to the innate immunity to retroviruses. In this manuscript, we systematically test the antiviral activities of 55 human and mouse TRIM proteins. The results are astonishingly complex with activities affecting both early and late stages of the retroviral life cycle. Importantly, a number of TRIM proteins that affect HIV or MLV replication upon overexpression, enhance virus entry or release when downregulated by gene silencing. These experiments suggest that additional TRIM proteins contribute to the endogenous restriction of retroviruses. Future work should focus on the identification of TRIM proteins that are upregulated specifically in response to interferons as well as the mechanisms by which the identified proteins interfere with retroviral replication.