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

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.

Keywords: HIV-1; TRIM5α; flaviviruses; innate immunity; ribonucleoprotein; ubiquitin.

Figure 1

The various interactions between TRIM5α and its targets. Flaviviruses enter the cell cytoplasm via endocytosis and create replication complexes anchored to modified membranes of the endoplasmic reticulum. (a) Recognition of the active flavivirus replication complex (yellow) by TRIM5α (blue) that leads to the ubiquitination (orange) and degradation of the viral RNA protease-helicase (green) via the proteasome (light grey). (b) Innate immune sensing and disruption of cytoplasmic assemblies of the retroelement LINE-1 (purple). (c) The retroviral capsid lattice (black) coated by hexagonal assemblies of TRIM5α. These higher-order TRIM5α oligomers not only induce premature uncoating of the retroviral genome, but also create a platform to promote a TRIM5α-mediated antiviral state via induction of NF-κB signaling.

Figure 2

The structurally diverse substrates detected by TRIM5α. TRIM5α has been shown to target and respond to viral proteins belonging to evolutionarily divergent virus families. (a) Representative structure of the active RNA helicase protein shared by members of the flavivirus genus. Shown here (colored in green) is a superposition of two crystal structures from the DENV NS3 protein bound to a substrate single stranded RNA (ssRNA) (PDB code: 5XC6) and its protease cofactor NS2B (shown in light grey) (PDB code: 2VBC). The individual domains of the protein and the recognition site for TRIM5α binding are indicated. (b) Trimeric ORF1 RNA-binding protein that is the main protein component of LINE-1 RNPs (shown in purple) (PDB code 2YKO). (c) Molecular modeling of a hexagonal TRIM5α assembly (outlined in light grey) bound to a lattice of HIV-1 capsid (dark grey) based on an electron density map recently resolved by electron tomography (ET) (EMD-20565). 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.