Abstract
Selective recognition and removal of faulty transcripts and misfolded polypeptides are crucial for cell viability. In eukaryotic cells, nonsense-mediated mRNA decay (NMD) constitutes an mRNA surveillance pathway for sensing and degrading aberrant transcripts harboring premature termination codons (PTCs). NMD functions also as a post-transcriptional gene regulatory mechanism by downregulating naturally occurring mRNAs. As NMD is activated only after a ribosome reaches a PTC, PTC-containing mRNAs inevitably produce truncated and potentially misfolded polypeptides as byproducts. To cope with the emergence of misfolded polypeptides, eukaryotic cells have evolved sophisticated mechanisms such as chaperone-mediated protein refolding, rapid degradation of misfolded polypeptides through the ubiquitin–proteasome system, and sequestration of misfolded polypeptides to the aggresome for autophagy-mediated degradation. In this review, we discuss how UPF1, a key NMD factor, contributes to the selective removal of faulty transcripts via NMD at the molecular level. We then highlight recent advances on UPF1-mediated communication between mRNA surveillance and protein quality control.
Highlights
In addition to premature termination codons (PTCs)-polypeptides, up-frameshift 1 (UPF1) contributes to the efficient formation of aggresomes containing other misfolded polypeptides that are irrelevant to PTC; these include (i) a mutant form of cystic fibrosis transmembrane conductance regulator harboring a single amino acid deletion at position 508 (CFTR-∆F508) [69,72,75] and (ii) puromycin-conjugated polypeptides generated upon puromycin treatment, which causes premature translation termination and releases truncated polypeptides in puromycinconjugated forms [98]
It has long been considered that UPF1 is a specific factor responsible for mRNA
Surveillance and other mRNA decay pathways [3]. In addition to this function, UPF1 contributes to protein quality control in several different ways: first, UPF1 degrades PTC-polypeptides in an nonsense-mediated mRNA decay (NMD)-coupled manner [49,50]
Summary
Ensuring the fidelity of genetic information is crucial for cell survival. In particular, the quality and quantity of mRNAs should be tightly managed because mRNAs transcribed from DNA are used as templates for protein synthesis [1]. It should be noted that, in addition to the faulty mRNAs containing PTCs, NMD can target naturally occurring normal mRNAs by acting as a post-transcriptional generegulatory mechanism [2]. These endogenous natural mRNAs targeted for NMD include mRNAs harboring upstream ORFs in the 5’-untranslated regions (5’UTRs), a long 3’UTR, exon junction complexes (EJCs) at the 3’UTR, or the UGA encoding selenocysteine within the ORF [2]. Such post-transcriptional regulation via NMD participates in successful adaptation to various intrinsic or extrinsic stresses as well as many cellular and biological. Biomedicines 2021, 9, 995 processes, such as cell differentiation, cell death, viral defense, and organismal development [7,8,9]
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