The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation

Agata N. Makar, Alina Boraman, Peter Mosen, Joanne E. Simpson, Jair Marques, Tim Michelberger, Stuart Aitken, Ann P. Wheeler, Dominic Winter, Alex Kriegsheim and Noor Gammoh ()
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Agata N. Makar: University of Edinburgh, Crewe Road South
Alina Boraman: University of Edinburgh, Crewe Road South
Peter Mosen: University of Bonn
Joanne E. Simpson: University of Edinburgh, Crewe Road South
Jair Marques: University of Edinburgh, Crewe Road South
Tim Michelberger: University of Edinburgh, Crewe Road South
Stuart Aitken: Crewe Road South, University of Edinburgh
Ann P. Wheeler: Crewe Road South, University of Edinburgh
Dominic Winter: University of Bonn
Alex Kriegsheim: University of Edinburgh, Crewe Road South
Noor Gammoh: University of Edinburgh, Crewe Road South

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Autophagy is a finely orchestrated process required for the lysosomal degradation of cytosolic components. The final degradation step is essential for clearing autophagic cargo and recycling macromolecules. Using a CRISPR/Cas9-based screen, we identify RNAseK, a highly conserved transmembrane protein, as a regulator of autophagosome degradation. Analyses of RNAseK knockout cells reveal that, while autophagosome maturation is intact, cargo degradation is severely disrupted. Importantly, lysosomal protease activity and acidification remain intact in the absence of RNAseK suggesting a specificity to autolysosome degradation. Analyses of lysosome fractions show reduced levels of a subset of hydrolases in the absence of RNAseK. Of these, the knockdown of PLD3 leads to a defect in autophagosome clearance. Furthermore, the lysosomal fraction of RNAseK-depleted cells exhibits an accumulation of the ESCRT-III complex component, VPS4a, which is required for the lysosomal targeting of PLD3. Altogether, here we identify a lysosomal hydrolase delivery pathway required for efficient autolysosome degradation.

Date: 2024
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DOI: 10.1038/s41467-024-52049-3

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