Identification of a Nonsense-Mediated Decay pathway at the Endoplasmic Reticulum

Abstract

AbstractNonsense-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. Here, we show that NBAS fulfils 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 co-regulate 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.Graphical AbstractHIGHLIGHTSNBAS is an NMD factor that localizes to the membrane of the endoplasmic reticulum (ER)NBAS has dual, independent, roles in Golgi-to-ER retrograde transport and in ER-NMDNBAS recruits the core NMD factor UPF1 to the membrane of the ERThe ER-NMD pathway targets for degradation mRNAs that are translated at the ER