Cells rely on ribosomes to efficiently translate genetic information into functional proteins, a process essential for cellular survival and function. Ribosomes attached to the endoplasmic reticulum (ER) are particularly critical, as they synthesize approximately 40% of the proteome, including secreted and membrane-bound proteins. However, under stress or due to aberrant mRNA, ribosomal collisions occur, leading to stalled translation and the accumulation of incomplete and toxic polypeptides. These disruptions jeopardize ER function and overall protein homeostasis, presenting a significant challenge in eukaryotic cells.
Autophagy, a conserved cellular degradation pathway, plays a central role in recycling damaged or dysfunctional cellular components. While much is known about autophagy's role in general quality control, its involvement in resolving stalled ribosomes at the ER remains poorly understood. Recent discoveries in our lab have identified two key autophagy receptors, C53 and VCS, that mediate the clearance of harmful byproducts of ribosomal stalling. These findings suggest the existence of a novel quality control mechanism—RiboRescuePhagy—that rescues ER-bound ribosomes by selectively degrading stalled translation products.
The primary objective of this project is to unravel the molecular mechanisms and physiological significance of autophagy-mediated ribosomal rescue. Specifically, we aim to:
Characterize the role of C53 in degrading incomplete polypeptides that arise from ribosome stalling at the ER.
Investigate how VCS targets harmful RNAs generated during ribosome collisions and its dual function as an mRNA decapping regulator and autophagy receptor.
Elucidate the role of ufmylation, a specialized post-translational modification, in regulating these autophagy pathways.
This research integrates advanced genetic screens, structural biology, and biochemical approaches in both model plants (Arabidopsis and Marchantia) and human cells. By defining how autophagy maintains ER ribosome functionality, this project addresses a fundamental gap in our understanding of cellular quality control.
Expected Impact
The outcomes of this project will redefine our understanding of autophagy as a ribosome-associated quality control mechanism, with broad implications across eukaryotic biology. This knowledge is expected to inform therapeutic strategies for diseases linked to ER stress and ribosomal dysfunction, including neurodegenerative disorders and metabolic syndromes. Additionally, insights into RiboRescuePhagy could enhance biotechnological applications such as optimizing protein production in plants, a key tool for sustainable agriculture and pharmaceuticals.
