Project description
A new mechanism of protein homeostasis
Cells constantly adjust the stability of their mRNAs to fine-tune protein production. While classical pathways rely on RNA-binding factors, a newly uncovered mechanism called peptide-mediated mRNA decay (PMD) links mRNA degradation directly to the nascent protein being synthesised. This process ensures that excess protein triggers selective destruction of its own transcript via factors that recognise the emerging polypeptide. Defects in PMD can disrupt cell division and neurodevelopment, and early evidence suggests it may also regulate transcripts encoding aggregation-prone proteins. The ERC-funded DECODE-PMD project will decipher how nascent peptides initiate decay. The identification of physiological triggers and PMD targets genome-wide will help establish a new paradigm for protein homeostasis.
Objective
Cells tightly regulate mRNA stability to ensure accurate gene expression across diverse cellular states and conditions. Traditionally, selective mRNA degradation has been attributed to the recognition of nucleotide sequence elements by proteins or small RNAs that subsequently recruit decay factors. Conversely, an emerging mechanism termed “peptide-mediated mRNA decay” (PMD) involves the encoded protein: my postdoctoral work revealed how the nascent polypeptide—physically linked to the mRNA during translation by the ribosome—can direct mRNA decay. This process is exemplified by tubulin mRNAs, which are selectively degraded when cells sense excess free tubulin levels. In this novel type of regulation, a recognition factor binds the nascent polypeptide to recruit downstream factors that trigger mRNA degradation. Impaired tubulin PMD results in severe phenotypes like defects in cell division and neurodevelopment. Beyond tubulins, emerging evidence points to critical PMD mechanisms targeting transcripts encoding aggregation-prone proteins. I postulate that PMD represents an entirely unexplored paradigm of gene regulation that dynamically adjusts protein production to ensure cellular fitness. However, the mechanistic understanding of PMD is still limited and the full range of substrates remains unknown.
In DECODE-PMD I will unravel how nascent polypeptides direct mRNA degradation on ribosomes and chart the transcriptome-wide map of PMD substrates. Specifically, I aim to (1) decode how mRNA translation and degradation are coupled during tubulin PMD using a biochemical reconstitution approach; (2) decipher the physiological triggers of tubulin PMD and its regulation; and (3) harness advanced sequencing methods to systematically identify PMD substrates and derive common mechanistic principles. Our innovative work will provide a conceptual framework for how cells exploit nascent polypeptide recognition for selective tuning of mRNA stability to maintain protein homeostasis.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics RNA
- medical and health sciences basic medicine physiology homeostasis
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2025-STG
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08003 Barcelona
Spain
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