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How does autophagy rescue stalled ribosomes?

Cel

Multiple ribosomes simultaneously move along the mRNAs to translate the genes into proteins. Cellular stress triggers collisions of ribosomes and disrupts protein synthesis. Eukaryotes have evolved multi-tiered quality control mechanisms that monitor ribosomes and rescue them on collision. While much is known about the rescue of cytosolic ribosomes, how the cell rescues stalled endoplasmic reticulum bound (ER-bound) ribosomes remains unknown. We recently discovered that the stalling of ER-bound ribosomes induces autophagy, a major cellular degradation pathway. We discovered two autophagy receptors that are induced upon stalling of ER-bound ribosomes and these proteins are conserved between plants and humans. We also showed that ufmylation, an elusive posttranslational modification system regulates ER-bound ribosome stalling-induced autophagy. These two discoveries indicate that autophagy plays a major role in the maintenance of a functional ER-bound ribosome population. Based on these discoveries, I hypothesize that autophagy rescues stalled ER-bound ribosomes by selectively degrading harmful polypeptides and RNAs that clog the ribosomes during collisions. Here, I propose to define and characterize this conserved quality control mechanism. I will establish a suite of complementary methods in the model plants Arabidopsis thaliana and Marchantia polymorpha to explore the physiological significance of autophagy-mediated ribosomal rescue (RiboRescuePhagy) in complex multicellular organisms. In parallel, I will carry out unbiased genetic screens in human cell lines to discover the molecular components that mediate RiboRescuePhagy. Finally, I will perform structure-function analysis of a key ufmylation enzyme to untangle the connection between ufmylation and autophagy. At the completion of this project, we will have defined a new quality control mechanism that rescues stalled ER-bound ribosomes to maintain cellular homeostasis in eukaryotes.

Dziedzina nauki (EuroSciVoc)

Słowa kluczowe

Program(-y)

Temat(-y)

System finansowania

HORIZON-ERC - HORIZON ERC Grants

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Zaproszenie do składania wniosków

(odnośnik otworzy się w nowym oknie) ERC-2021-COG

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Instytucja przyjmująca

RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Wkład UE netto
€ 338 744,14
Adres
SEMINARSTRASSE 2
69117 Heidelberg
Niemcy
Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Rodzaj działalności
Higher or Secondary Education Establishments
Linki
Koszt całkowity
€ 338 744,14

Beneficjenci (2)