Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>Translational reprogramming allows organisms to adapt to changing conditions. Upstream start codons (uAUGs), which are prevalently present in mRNAs, have crucial roles in regulating translation by providing alternative translation start sites<jats:sup>1–4</jats:sup>. However, what determines this selective initiation of translation between conditions remains unclear. Here, by integrating transcriptome-wide translational and structural analyses during pattern-triggered immunity in <jats:italic>Arabidopsis</jats:italic>, we found that transcripts with immune-induced translation are enriched with upstream open reading frames (uORFs). Without infection, these uORFs are selectively translated owing to hairpins immediately downstream of uAUGs, presumably by slowing and engaging the scanning preinitiation complex. Modelling using deep learning provides unbiased support for these recognizable double-stranded RNA structures downstream of uAUGs (which we term uAUG-ds) being responsible for the selective translation of uAUGs, and allows the prediction and rational design of translating uAUG-ds. We found that uAUG-ds-mediated regulation can be generalized to human cells. Moreover, uAUG-ds-mediated start-codon selection is dynamically regulated. After immune challenge in plants, induced RNA helicases that are homologous to Ded1p in yeast and DDX3X in humans resolve these structures, allowing ribosomes to bypass uAUGs to translate downstream defence proteins. This study shows that mRNA structures dynamically regulate start-codon selection. The prevalence of this RNA structural feature and the conservation of RNA helicases across kingdoms suggest that mRNA structural remodelling is a general feature of translational reprogramming.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear<jats:sup>1</jats:sup>. Because ICB targets cell–cell interactions<jats:sup>2</jats:sup>, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry<jats:sup>3</jats:sup> to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, <jats:italic>n</jats:italic> = 243; early on-treatment, <jats:italic>n</jats:italic> = 207; post-treatment, <jats:italic>n</jats:italic> = 210). Multivariate modelling showed that the fractions of proliferating CD8<jats:sup>+</jats:sup>TCF1<jats:sup>+</jats:sup>T cells and MHCII<jats:sup>+</jats:sup> cancer cells were dominant predictors of response, followed by cancer–immune interactions with B cells and granzyme B<jats:sup>+</jats:sup> T cells. On-treatment, responsive tumours contained abundant granzyme B<jats:sup>+</jats:sup> T cells, whereas resistant tumours were characterized by CD15<jats:sup>+</jats:sup> cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.</jats:p>