Τρίτη 28 Φεβρουαρίου 2017

Expanded Polyalanine Tracts Function as Nuclear Export Signals and Promote Protein Mislocalization via Eukaryotic Translation Elongation Factor 1 Alpha 1 [Cell Biology]

Polyalanine (polyA) diseases are caused by the expansion of translated GCN triplet nucleotide sequences encoding polyA tracts in proteins. To date, nine human disorders have been found to be associated with polyA tract expansions, including congenital central hypoventilation syndrome and oculopharyngeal muscular dystrophy. Previous studies have demonstrated that unexpanded wild-type polyA-containing proteins localize to the cell nucleus, while expanded polyA-containing proteins primarily localize to the cytoplasm. As most of these polyA disease proteins are transcription factors, this mislocalization causes cellular transcriptional dysregulation leading to cellular dysfunction. Correcting this faulty localization could potentially point to strategies to treat the aforementioned disorders, so there is a pressing need to identify the mechanisms underlying the mislocalization of expanded polyA protein. Here, we performed a glutathione-S-transferase pull-down assay followed by mass spectrometry and identified eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) as an interacting partner with expanded polyA-containing proteins. Strikingly, knockdown of eEF1A1 expression partially corrected the mislocalization of the expanded polyA proteins in the cytoplasm and restored their functions in the nucleus. We further demonstrated that the expanded polyA domain itself can serve as a nuclear export signal. Taken together, this study demonstrates that eEF1A1 regulates the subcellular location of expanded polyA proteins and is therefore a potential therapeutic target for combating the pathogenesis of polyA diseases.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2mblvkA
via IFTTT

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Δημοφιλείς αναρτήσεις