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.
Highlights
Misfolded polypeptides are rapidly cleared from cells via the ubiquitin–proteasome system (UPS)
Our previous report revealed that endogenous CTIF is localized to the cytoplasmic side of the perinuclear region, supporting our model that CTIF is loaded onto the 50-end of newly synthesized mRNAs that are being exported from the nucleus to the cytoplasm through the nuclear pore complex[6]
microtubule-organizing centre (MTOC) is the cellular site of aggresome formation, where small cytoplasmic aggregates of misfolded polypeptides are sequestered and eventually degraded by aggrephagy[22,23,24]
Summary
Misfolded polypeptides are rapidly cleared from cells via the ubiquitin–proteasome system (UPS). Misfolded polypeptides are degraded by the ubiquitin–proteasome system (UPS), preventing their accumulation within cells When these two initial processes are overwhelmed or impaired, the misfolded polypeptides are prone to forming small cytoplasmic aggregates[22,23,24]. HDAC6 binds to unanchored ubiquitin C-terminal tails in the misfolded polypeptides through its C-terminal binder of ubiquitin zinc-finger/zinc-finger-ubiquitin-specific processing protease (ZnF-UBP) domain, and associates with dynein motors through its N-terminal dynein motor-binding domain[27,32] Through these interactions, HDAC6 functions as a molecular adaptor to link misfolded polypeptide-containing small cytoplasmic aggregates to dynein motors, triggering the efficient movement of the aggregates to the aggresome
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
