Co-option of endogenous viral sequences for host cell function

Abstract

Eukaryotic genomes are littered with sequences of diverse viral origins, termed endogenous viral elements (EVEs). Here we used examples primarily drawn from mammalian endogenous retroviruses to document how the influx of EVEs has provided a source of prefabricated coding and regulatory sequences that were formerly utilized for viral infection and replication, but have been occasionally repurposed for cellular function. While EVE co-option has benefited a variety of host biological functions, there appears to be a disproportionate contribution to immunity and antiviral defense. The mammalian embryo and placenta offer opportunistic routes of viral transmission to the next host generation and as such they represent hotbeds for EVE cooption. Based on these observations, we propose that EVE cooption is initially driven as a mean to mitigate conflicts between host and viruses, which in turn acts as a stepping-stone toward the evolution of cellular innovations serving host physiology and development.

Figure 1. Direct interference of EVE proteins with exogenous viral replication

Coopted EVE proteins can compete with virus replication by binding cellular proteins otherwise bound by exogenous virus (A). Physical interactions between coopted EVE proteins and homologous (B) or non-homologous (C) proteins encoded by exogenous viruses can result in dominant-negative effects on virus replication.

Figure 2. Mechanisms of EVE co-option for antiviral immunity and cell physiology

A prototypical retroviral life cycle (shown in red) proceeds through cell entry (ENTRY), reverse transcription (RT), chromosomal integration (INT), proviral transcription (TX), translation (TL) and particle assembly (AS). EVE-encoded proteins and RNAs (shown in purple) can interfere with many steps of virus replication. EVE-encoded proteins may block virus entry (Env), provirus release (Gag), virus genome replication, and capsid assembly (Gag). Small RNAs (piRNAs, siRNAs) derived from EVE loci may also repress virus expression transcriptionally or post-transcriptionally. EVEs can also mediate cell fusion (Env) and may be involved in intercellular signaling (Gag). Viral proteins and nucleic acids can be recognized by host innate immune sensors (shown in blue) resulting in stimulation of the innate immune response.

Figure 3. Coopted EVEs affect host gene expression by diverse mechanisms

(A) EVE sequences may function as cis-regulatory DNA elements such as enhancers or promoters. (B) EVE-derived lncRNAs can also affect gene expression by acting as co-transcriptional regulators (C) or miRNA sponges (D). EVE-encoded proteins may also regulate gene expression. For instance, Rec and Gag proteins may bind to and modulate host mRNA stability, localization, or translation.