Transcriptome-wide mRNA condensation precedes stress granule formation and excludes stress-induced transcripts

bioRxiv. 2024 May 2:2024.04.15.589678. doi: 10.1101/2024.04.15.589678.

Hendrik Glauninger ¹ ², Jared A M Bard ³, Caitlin J Wong Hickernell ⁴, Edo M Airoldi ⁵, Weihan Li ⁶, Robert H Singer ⁶ ⁷ ⁸, Sneha Paul ⁴, Jingyi Fei ⁴ ⁹, Tobin R Sosnick ⁴ ⁹ ¹⁰, Edward W J Wallace ¹¹, D Allan Drummond ⁴ ⁹ ¹²

Affiliations

1 Graduate Program in Biophysical Sciences, The University of Chicago, Chicago, IL, USA.
2 Interdisciplinary Scientist Training Program, The University of Chicago, Chicago, IL, USA.
3 Department of Biology, Texas A&M University, College Station, TX, USA.
4 Department of Biochemistry & Molecular Biology, The University of Chicago, Chicago, IL, USA.
5 Fox School of Business and Management, Temple University, Philadelphia, PA, USA.
6 Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
7 Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
8 Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
9 Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
10 Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
11 School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland, UK.
12 Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, IL, USA.

PMID: 38659805 DOI: 10.1101/2024.04.15.589678

Abstract

Stress-induced condensation of mRNA and proteins into stress granules is conserved across eukaryotes, yet the function, formation mechanisms, and relation to well-studied conserved transcriptional responses remain largely unresolved. Stress-induced exposure of ribosome-free mRNA following translational shutoff is thought to cause condensation by allowing new multivalent RNA-dependent interactions, with RNA length and associated interaction capacity driving increased condensation. Here we show that, in striking contrast, virtually all mRNA species condense in response to multiple unrelated stresses in budding yeast, length plays a minor role, and instead, stress-induced transcripts are preferentially excluded from condensates, enabling their selective translation. Using both endogenous genes and reporter constructs, we show that translation initiation blockade, rather than resulting ribosome-free RNA, causes condensation. These translation initiation-inhibited condensates (TIICs) are biochemically detectable even when stress granules, defined as microscopically visible foci, are absent or blocked. TIICs occur in unstressed yeast cells, and, during stress, grow before the appearance of visible stress granules. Stress-induced transcripts are excluded from TIICs primarily due to the timing of their expression, rather than their sequence features. Together, our results reveal a simple system by which cells redirect translational activity to newly synthesized transcripts during stress, with broad implications for cellular regulation in changing conditions.

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