In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 18, No. 4 ( 2022-4-29), p. e1010185-
Kurzfassung:
The alpha subunit of the cytoplasmic Phenylalanyl tRNA synthetase (α-PheRS, FARSA in humans) displays cell growth and proliferation activities and its elevated levels can induce cell fate changes and tumor-like phenotypes that are neither dependent on the canonical function of charging tRNA Phe with phenylalanine nor on stimulating general translation. In intestinal stem cells of Drosophila midguts, α-PheRS levels are naturally slightly elevated and human FARSA mRNA levels are elevated in multiple cancers. In the Drosophila midgut model, elevated α-PheRS levels caused the accumulation of many additional proliferating cells resembling intestinal stem cells (ISCs) and enteroblasts (EBs). This phenotype partially resembles the tumor-like phenotype described as Notch RNAi phenotype for the same cells. Genetic interactions between α-PheRS and Notch suggest that their activities neutralize each other and that elevated α-PheRS levels attenuate Notch signaling when Notch induces differentiation into enterocytes, type II neuroblast stem cell proliferation, or transcription of a Notch reporter. These non-canonical functions all map to the N-terminal part of α-PheRS which accumulates naturally in the intestine. This truncated version of α-PheRS (α-S) also localizes to nuclei and displays weak sequence similarity to the Notch intracellular domain (NICD), suggesting that α-S might compete with the NICD for binding to a common target. Supporting this hypothesis, the tryptophan (W) residue reported to be key for the interaction between the NICD and the Su(H) BTD domain is not only conserved in α-PheRS and α-S, but also essential for attenuating Notch signaling.
Materialart:
Online-Ressource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010185
DOI:
10.1371/journal.pgen.1010185.g001
DOI:
10.1371/journal.pgen.1010185.g002
DOI:
10.1371/journal.pgen.1010185.g003
DOI:
10.1371/journal.pgen.1010185.g004
DOI:
10.1371/journal.pgen.1010185.g005
DOI:
10.1371/journal.pgen.1010185.g006
DOI:
10.1371/journal.pgen.1010185.g007
DOI:
10.1371/journal.pgen.1010185.t001
DOI:
10.1371/journal.pgen.1010185.t002
DOI:
10.1371/journal.pgen.1010185.t003
DOI:
10.1371/journal.pgen.1010185.s001
DOI:
10.1371/journal.pgen.1010185.s002
DOI:
10.1371/journal.pgen.1010185.s003
DOI:
10.1371/journal.pgen.1010185.s004
DOI:
10.1371/journal.pgen.1010185.s005
DOI:
10.1371/journal.pgen.1010185.s006
DOI:
10.1371/journal.pgen.1010185.s007
DOI:
10.1371/journal.pgen.1010185.r001
DOI:
10.1371/journal.pgen.1010185.r002
DOI:
10.1371/journal.pgen.1010185.r003
DOI:
10.1371/journal.pgen.1010185.r004
DOI:
10.1371/journal.pgen.1010185.r005
DOI:
10.1371/journal.pgen.1010185.r006
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2022
ZDB Id:
2186725-2
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