Abstract
The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.
Highlights
The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear
We previously described T. brucei VEX1 (Tb927.11.16920), the only known protein enriched in association with the ESB17
VEX1, is at the heart of the nuclear subdomain meditating antigenic variation in trypanosomes, but VEX1 lacks orthologs in other cell types, it remained unclear why variant surface glycoprotein (VSG)-exclusion was only partially perturbed following VEX1-knockdown and it remained unclear whether other factors were involved in VSG-exclusion
Summary
The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. The VEX2-orthologue and CAF-1 in mammals are implicated in exclusion and inheritance functions In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy. The African trypanosome, Trypanosoma brucei, is transmitted among mammalian hosts by tsetse-flies and, due to effective immune evasion, causes chronic and lethal infections, sleeping-sickness in humans and nagana in cattle In these parasites RNA polymerase-I (pol-I) transcribes a single, dominant, telomeric variant surface glycoprotein (VSG) gene[3] as part of a polycistronic transcription unit. The complex assembles a sub-nuclear domain in a transcriptiondependent manner and maintains VSG allelic exclusion by negatively controlling transcription of other telomeric VSGs. Inheritance of VSG exclusion requires maintenance of the VEXcomplex during S-phase, which depends upon the conserved chromatin assembly factor, CAF-1
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