Nonsense-mediated mRNA decay (NMD) typifies an mRNA surveillance pathway. Because NMD necessitates a translation event to recognize a premature termination codon on mRNAs, truncated misfolded polypeptides (NMD-polypeptides) could potentially be generated from NMD substrates as byproducts. Here, we show that when the ubiquitin–proteasome system is overwhelmed, various misfolded polypeptides including NMD-polypeptides accumulate in the aggresome: a perinuclear nonmembranous compartment eventually cleared by autophagy. Hyperphosphorylation of the key NMD factor UPF1 is required for selective targeting of the misfolded polypeptide aggregates toward the aggresome via the CTIF–eEF1A1–DCTN1 complex: the aggresome-targeting cellular machinery. Visualization at a single-particle level reveals that UPF1 increases the frequency and fidelity of movement of CTIF aggregates toward the aggresome. Furthermore, the apoptosis induced by proteotoxic stresses is suppressed by UPF1 hyperphosphorylation. Altogether, our data provide evidence that UPF1 functions in the regulation of a protein surveillance as well as an mRNA quality control.
Bibliographical noteFunding Information:
We thank Drs. Akio Yamashita and Shigeo Ohno for providing the α-SMG6 antibody, Dr. Jens Lykke-Andersen for plasmid pCMV-Myc-DCP1A, and Dr. Ron R. Kopito for the plasmid expressing GFP-CFTR-ΔF508. This work was supported by a National Research Foundation (NRF) of Korea grant funded by the Korean government (Ministry of Science, ICT and Future Planning; NRF-2015R1A3A2033665 and NRF-2018R1A5A1024261 to Y.K.K.; and NRF-2017K1A1A2013241 to J.-B.L.) and by a Korea University Future Research grant to Y.K.K.; Y.P. was supported in part by the NRF funded by the Ministry of Education (NRF-2019R1A6A3A13094238).
© 2020, The Author(s).
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)