From Capsids to Complexes: Expanding the Role of TRIM5α in the Restriction of Divergent RNA Viruses and Elements.

Kevin M Rose,Vanessa M Hirsch,Stephanie J Spada,Fadila Bouamr,Rebecca Broeckel,Kristin L Mcnally,Sonja M Best

doi:10.3390/v13030446

Kevin M Rose, Vanessa M Hirsch + Show 5 more

Open Access

https://doi.org/10.3390/v13030446

Copy DOI

Abstract

An evolutionary arms race has been ongoing between retroviruses and their primate hosts for millions of years. Within the last century, a zoonotic transmission introduced the Human Immunodeficiency Virus (HIV-1), a retrovirus, to the human population that has claimed the lives of millions of individuals and is still infecting over a million people every year. To counteract retroviruses such as this, primates including humans have evolved an innate immune sensor for the retroviral capsid lattice known as TRIM5α. Although the molecular basis for its ability to restrict retroviruses is debated, it is currently accepted that TRIM5α forms higher-order assemblies around the incoming retroviral capsid that are not only disruptive for the virus lifecycle, but also trigger the activation of an antiviral state. More recently, it was discovered that TRIM5α restriction is broader than previously thought because it restricts not only the human retroelement LINE-1, but also the tick-borne flaviviruses, an emergent group of RNA viruses that have vastly different strategies for replication compared to retroviruses. This review focuses on the underlying mechanisms of TRIM5α-mediated restriction of retroelements and flaviviruses and how they differ from the more widely known ability of TRIM5α to restrict retroviruses.

Highlights

The innate immune system evolved as an intracellular response to a variety of pathogens including viruses, bacteria, and fungi [1]
TRIM5α is a E3 ubiquitin ligase that belongs to the tripartite motif (TRIM) family of proteins that is recognized to include approximately 100 members, many of which participate in innate immune signaling [6,7]
Since its discovery over a decade ago, it was believed that the sole function of TRIM5α was to restrict retroviruses like HIV-1

Summary

Introduction

The innate immune system evolved as an intracellular response to a variety of pathogens including viruses, bacteria, and fungi [1]. By virtue of the same mechanism, TRIM69 has been shown to restrict Dengue virus (DENV), a mosquito-borne flavivirus, by binding to the viral protease-helicase NS3 and degrading it via the ubiquitin proteasome system [27]. This exact antiviral response was demonstrated by the potent restriction of several emergent tick-borne flaviviruses by TRIM5α [28] (Figure 1a). Capsid monomers and TRIM5α dimers and trimers were manually placed into the density using known structures of capsid (PDB code: 3J34) and molecular models, respectively

Recognition of Distinct Viral Ribonucleoproteins in Separate

Evasion of TRIM5α Surveillance

Conclusions