Misfolded polypeptides are selectively recognized and transported toward aggresomes by a CED complex

Joori Park, Yeonkyoung Park, Incheol Ryu, Mi-Hyun Choi, Hyo Jin Lee, Nara Oh, Kyutae Kim, Kyoung Mi Kim, Junho Choe, Cheolju Lee, Ja-Hyun Baik and Yoon Ki Kim ()
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Joori Park: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University
Yeonkyoung Park: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University
Incheol Ryu: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University
Mi-Hyun Choi: Korea University
Hyo Jin Lee: Korea University
Nara Oh: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University
Kyutae Kim: Korea University
Kyoung Mi Kim: Korea University
Junho Choe: Korea University
Cheolju Lee: BRI, Korea Institute of Science and Technology
Ja-Hyun Baik: Korea University
Yoon Ki Kim: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Misfolded polypeptides are rapidly cleared from cells via the ubiquitin–proteasome system (UPS). However, when the UPS is impaired, misfolded polypeptides form small cytoplasmic aggregates, which are sequestered into an aggresome and ultimately degraded by aggrephagy. Despite the relevance of the aggresome to neurodegenerative proteinopathies, the molecular mechanisms underlying aggresome formation remain unclear. Here we show that the CTIF–eEF1A1–DCTN1 (CED) complex functions in the surveillance of either pre-existing or newly synthesized polypeptides by linking two molecular events: selective recognition and aggresomal targeting of misfolded polypeptides. These events are accompanied by CTIF sequestration into the aggresome, preventing the additional synthesis of misfolded polypeptides from mRNAs bound by nuclear cap-binding complex. These events render cells more resistant to apoptosis induced by proteotoxic stresses. Collectively, our data provide compelling evidence for a previously unappreciated protein surveillance pathway and a regulatory gene expression network for coping with misfolded polypeptides.

Date: 2017
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DOI: 10.1038/ncomms15730

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