Nonsense-mediated mRNA decay factor UPF1 promotes aggresome formation

Abstract

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.

UPF1: From mRNA Surveillance to Protein Quality Control

“…Second, UPF1 acts as an E3 ligase to degrade target proteins in an NMD-independent manner [68]. Third, UPF1 senses the CED complex associated with misfolded polypeptides, and guides it to move toward the aggresome in an NMD-independent manner [76]. Thus, UPF1 ensures proper gene expression and protects the cells against the accumulation of misfolded polypeptides (Figure 3).…”

“…As PTC-containing mRNAs targeted for NMD always generate truncated nascent polypeptides (PTC-polypeptides) as byproducts [57,97], such potentially misfolded polypeptides can be transported toward the aggresome upon UPS impairment. Indeed, a recent study showed that PTC-polypeptides generated from a reporter NMD substrate (glutathione peroxidase 1 mRNA harboring a PTC) are enriched in aggresomes after treating cells with MG132, a potent proteasome inhibitor [76]. This observation suggested a possible crosstalk between the NMD pathway and aggresome formation.…”

“…BAG3 contains the PxxP and BAG domains, which interact with dynein and HSP70, respectively, stimulating aggresomal targeting of both polyubiquitinated and non-polyubiquitinated polypeptides [73,74]. The CED complex is engaged in the polyubiquitination-dependent formation of an aggresome containing misfolded polypeptides [75][76][77]. Originally, eEF1A1, a component of the CED complex, was characterized as a translation elongation factor that interacts with aminoacyl-tRNA to deliver it to the A site of ribosomes in a GTP-dependent manner [78].…”

“…Various studies have attempted to understand the molecular mechanism underlying UPF1-mediated aggresome formation. Based on the fact that efficient NMD is dependent on a continuous cycle of phosphorylation and dephosphorylation of UPF1, Park et al (2020) investigated the possible role of UPF1 phosphorylation in aggresome formation [76]. First, they noted that aggresomal targeting of UPF1 was dependent on its phosphorylation status.…”

A divergent nonsense-mediated decay machinery inPlasmodium falciparumis inefficient and non-essential

“…4B). P-bodies are conserved ribonucleoprotein granules that contain translationally repressed mRNAs, and mRNA decay factors including proteins involved in NMD (20,39).…”