Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Li S,Wu Z,Tantray I,Li Y,Chen S,Dong J,Glynn S,Vogel H,Snyder M,Lu Bdoi
10.1073/pnas.2005506117subject
Has Abstractpub_date
2020-10-06 00:00:00pages
25104-25115issue
40eissn
0027-8424issn
1091-6490pii
2005506117journal_volume
117pub_type
杂志文章abstract::Mitochondria isolated from maize plants with S-type male-sterile cytoplasms are capable of synthesizing four species of RNA at concentrations of actinomycin D that eliminate all DNA-directed RNA synthesis. No RNA synthesis occurs under the same conditions with mitochondria from plants possessing normal (N) cytoplasm o...
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