Identification of a localized nonsense-mediated decay pathway at the endoplasmic reticulum

Abstract

Nonsense-mediated decay (NMD) is a translation-dependent RNA quality control mechanism that occurs in the cytoplasm. However, it is unknown how NMD regulates the stability of RNAs translated at the endoplasmic reticulum (ER). Here, we identify a localized NMD pathway dedicated to ER-translated mRNAs. We previously identified NBAS, a component of the Syntaxin 18 complex involved in Golgi-to-ER trafficking, as a novel NMD factor. Furthermore, we show that NBAS fulfills an independent function in NMD. This ER-NMD pathway requires the interaction of NBAS with the core NMD factor UPF1, which is partially localized at the ER in the proximity of the translocon. NBAS and UPF1 coregulate the stability of ER-associated transcripts, in particular those associated with the cellular stress response. We propose a model where NBAS recruits UPF1 to the membrane of the ER and activates an ER-dedicated NMD pathway, thus providing an ER-protective function by ensuring quality control of ER-translated mRNAs.

An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay

“…We show that induction of ER stress with thapsigargin induces UPF1LL-dependent downregulation of hundreds of transcripts, a population particularly enriched for mRNAs encoding proteins trafficked through the ER. The extent to which UPF1LL complements or collaborates with IRE1mediated mRNA decay or the recently identified ER-associated NMD factor NBAS will require further study (Hollien & Weissman, 2006;Longman et al, 2020), but our data suggest that UPF1LL may help to relieve proteotoxic stress by reducing the abundance of transcripts encoding proteins with complex biosynthetic needs.…”

Poison Exon Splicing Regulates a Coordinated Network of SR Protein Expression during Differentiation and Tumorigenesis

“…Interestingly, the TRA2b-RRM-only mutant localized to the nucleus and perinuclear cytoplasmic inclusions. Specific RBPs have a role in stress granule formation (Markmiller et al, 2018) or trafficking of NMD transcripts to the endoplasmic reticulum (Longman et al, 2020), but whether TRA2b has a similar role or functions in the cytoplasm remains unknown. Additionally, our study demonstrates that TRA2b influences AS of its own PE with and without direct binding from its RRM domain, which may provide regulatory activity in addition to binding specificity.…”

Nonsense-Mediated mRNA Decay, a Finely Regulated Mechanism

“…This has notably been highlighted in a recent study showing that part of the NMD machinery localizes to the translocon, which sends newly synthesized proteins to the ER lumen. NMD thus ensures quality control of the mRNAs translated there [ 50 ].…”