Quality-control mechanisms targeting translationally stalled and C-terminally extended poly(GR) associated with ALS/FTD.
Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing-like activity in metazoans remain unclear. Here we show that CAT-tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated GGGGCC (G4C2) repeat expansion in C9ORF72, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to be cotranslationally imported into mitochondria. However, poly(GR) translation on mitochondrial surface is frequently stalled, triggering RQC and CAT-tailing-like C-terminal extension (CTE). CTE promotes poly(GR) stabilization, aggregation, and toxicity. Our genetic studies in Drosophila uncovered an important role of the mitochondrial protease YME1L in clearing poly(GR), revealing mitochondria as major sites of poly(GR) metabolism. Moreover, the mitochondria-associated noncanonical Notch signaling pathway impinges on the RQC machinery to restrain poly(GR) accumulation, at least in part through the AKT/VCP axis. The conserved actions of YME1L and noncanonical Notch signaling in animal models and patient cells support their fundamental involvement in ALS/FTD.
['Li|Shuangxi|S|', 'Wu|Zhihao|Z|', 'Tantray|Ishaq|I|', 'Li|Yu|Y|', 'Chen|Songjie|S|0000-0002-9568-5705', 'Dong|Jason|J|0000-0001-8809-5187', 'Glynn|Steven|S|', 'Vogel|Hannes|H|', 'Snyder|Michael|M|', 'Lu|Bingwei|B|']
D000074183:ATPases Associated with Diverse Cellular Activities D000690:Amyotrophic Lateral Sclerosis D000818:Animals D001120:Arginine D000073885:C9orf72 Protein D042622:DNA Repeat Expansion D004195:Disease Models, Animal D029721:Drosophila Proteins D004331:Drosophila melanogaster D057180:Frontotemporal Dementia D057809:HEK293 Cells D006801:Humans D008666:Metalloendopeptidases D008928:Mitochondria D024101:Mitochondrial Proteins D014176:Protein Biosynthesis D020543:Proteome D051880:Receptors, Notch D012270:Ribosomes D015398:Signal Transduction
ribosome-associated quality control CAT-tailing YME1L Notch C9-ALS/FTD