Translation regulation during pattern-triggered immunity

Abstract

Translational reprogramming allows organisms to adapt to changing conditions. In regulating translation, upstream start codons (uAUGs), prevalently present in mRNAs, play crucial roles by providing alternative translation start sites. However, what determines this selective translation initiation between conditions remains a fundamental question. By integrating transcriptome-wide translational and structural analyses during Arabidopsis pattern-triggered immunity, I found that transcripts with immune-induced translation are enriched with upstream open reading frames (uORFs). Under normal conditions, these uORFs are selectively translated due to highly structured regions immediately downstream of uAUGs by slowing and engaging the scanning preinitiation complex. Deep learning modelling provides unbiased support for recognizable double-stranded RNA structures downstream of uAUGs (“uAUG-ds”) being responsible for the selective translation of uAUGs. I showed that uAUG-ds regulation is generalizable in human cells. Moreover, I found that uAUG-ds-mediated start codon selection is dynamically regulated. Upon immune challenge in plants, induced Ded1p/DDX3X-homologous RNA helicases resolve these structures, allowing ribosomes to bypass uAUGs to translate downstream defensce proteins. This study demonstrates that mRNA structures, rather than primary sequences, dynamically regulate start codon selection. The prevalence of this RNA structural feature and the conservation of RNA helicases across kingdoms suggest the generality of mRNA structural remodelling in mediating translational reprogramming.