Publications
6 October 2026
Initiation codon context governs translation-coupled mRNA decay and coordinated expression in the human parasite Leishmania
Abstract
In the absence of
canonical transcriptional regulation, Leishmania expression changes
largely rely on post-transcriptional control via differential mRNA turnover,
yet how this process is linked to translation-dependent decay remains poorly
understood. Here, by using the initiation codon sequence context as a molecular
entry point, we uncover that Kozak-mediated changes in translational efficiency
affect mRNA stability. Genome-wide mapping of Kozak sequences across pathogenic
trypanosomatids revealed evolutionary adaptation of this cis-regulatory
element at the genus and sub-genus levels, as judged by the selective
enrichment of only a small subset of possible Kozak motifs that clustered in a
species-specific fashion. Transgenic expression of EGFP under the control of
distinct Kozak variants correlated EGFP mRNA recruitment to monosomes and heavy
polysomes with respectively decreased and increased protein abundance.
Surprisingly, this correlation also extended to EGFP transcript abundance,
suggesting a role of the Kozak motif in translation-mediated mRNA turnover.
Transcript profiling of parasites arrested for either transcription or
translation elongation revealed a subset of unstable mRNAs that were rescued
from decay in a translation-dependent fashion. Significantly, these transcripts
contained a characteristic Kozak motif further supporting a possible role of
the initiation codon sequence context in co-regulation of translation-mediated
mRNA decay. Our work uncovers a key role for translation initiation-coupled
mRNA decay in Leishmania gene expression regulation, adding a previously
under-appreciated layer of post-transcriptional regulation in parasite
adaptation.