Identification of a 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. 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 Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/954453v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@172e4a3org.highwire.dtl.DTLVardef@9769org.highwire.dtl.DTLVardef@d478c1org.highwire.dtl.DTLVardef@143e0f9_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LINBAS is an NMD factor that localizes to the membrane of the endoplasmic reticulum (ER) C_LIO_LINBAS has dual, independent, roles in Golgi-to-ER retrograde transport and in ER-NMD C_LIO_LINBAS recruits the core NMD factor UPF1 to the membrane of the ER C_LIO_LIThe ER-NMD pathway targets for degradation mRNAs that are translated at the ER C_LI