Dot1 triggers a conserved ribophagy signal to govern ribosome quality and longevity by methylating Rpl12.
Abstract
Ribophagy plays a critical role in maintaining ribosome quality, yet how ribosomes are marked for autophagic recognition remains poorly understood. Here, we identify the methyltransferase Dot1/DOT1L as a conserved regulator of ribophagy that generates an "eat-me" signal through methylation of Rpl12, thereby regulating ribosome quality. Under nutrient deprivation, Dot1 methylates Rpl12 at K41 and K48 in Saccharomyces cerevisiae, enhancing its interaction with Atg11 and initiating ribophagy through the TOR-Atg1-Rpl12 signaling axis. In mammals, starvation induces partial cytoplasmic translocation of DOT1L, where it colocalizes with and methylates RPL12. In Drosophila, ribosomes incorporating Gpp (the Dot1 homolog)-methylated RpL12 show strong colocalization with the autophagosome marker Atg8a. Flies carrying methylation-deficient RpL12 mutants exhibit impaired ribophagy, developmental abnormalities, accelerated aging, muscle degeneration, and reduced stress resistance. Collectively, these findings reveal that Dot1-mediated Rpl12 methylation generates a conserved "eat-me" signal that links nutrient availability to ribosome quality control and lifespan regulation.
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Research summary
Dot1-mediated methylation of Rpl12 acts as a conserved "eat-me" signal that initiates ribophagy to maintain ribosome quality and regulate lifespan. This paper is relevant because it identifies a specific molecular mechanism linking nutrient sensing to ribosome quality control, a fundamental process in cellular homeostasis, and demonstrates that defects in this pathway lead to accelerated aging and reduced stress resistance in model organisms, thereby addressing a root cause of aging rather than a symptom.
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