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

Dasa Longman,Robert S Young,Javier F Cáceres,Nele Hug,Dimitrios K Papadopoulos,Magdalena M Maslon,Jack J Stoddart,Martin S Taylor,Laura C Murphy,Kathryn A Jackson-Jones

doi:10.1101/gad.338061.120

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.

Highlights

The nonsense-mediated decay (NMD) pathway is a highly conserved surveillance mechanism that targets mRNAs harboring premature termination codons (PTCs) for degradation
Current efforts have focused on the mechanism and regulation of cytoplasmic NMD; it is largely unknown how this mechanism operates on mRNAs that are translated at the endoplasmic reticulum (ER), which, due to their intrinsic localized translation, will not have sufficient exposure to cytoplasmic NMD
We demonstrate that NBAS recruits the core NMD factor UPF1 to the membrane of the ER and promotes the degradation of NMD substrates that are translated at the ER

Summary

Introduction

The nonsense-mediated decay (NMD) pathway is a highly conserved surveillance mechanism that targets mRNAs harboring premature termination codons (PTCs) for degradation. Using RNAi screens in C. elegans, we previously identified several novel NMD factors that were essential for viability, suggesting that they fulfill additional functions in nematodes, where this pathway is not essential (Longman et al 2007; Casadio et al 2015). There is a precedent for a localized NMD response in neurons, where NMD regulates the expression of both dendritic and axonal mRNAs upon their activation of localized mRNA translation (Giorgi et al 2007; Colak et al 2013) Both NBAS and a second novel NMD factor identified in our RNAi screens, SEC13 (nuclear pore and COPII coat complex component), localize to the membrane of the ER, raising the possibility that they could be involved in an ER-localized NMD pathway (Longman et al 2007; Casadio et al 2015)

Methods

Results

Conclusion