LMS Seminar Series – Javier Caceres
Nonsense-mediated decay: RNA-quality control of gene expression in health and disease
The Nonsense-mediated decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs) but also regulates the abundance of a large number of endogenous RNAs and fine-tunes many physiological processes. Using genome-wide RNAi screens, we identified several novel NMD factors, including the RNA helicase DHX34 and NBAS (Neuroblastoma Amplified Sequence) and demonstrated that they act in concert with core NMD factors to co-regulate a large number of endogenous RNA targets. Most studies to date have focused on cytoplasmic NMD; however, it is largely unknown how this mechanism operates on transcripts encoding secreted or ER-resident proteins. We have uncovered evidence that suggests the existence of an NMD pathway dedicated to Endoplasmic Reticulum (ER)-localized mRNAs, which involves two NMD factors that localize to the ER, NBAS and SEC13. In agreement NBAS RNA targets are enriched for ER-associated transcripts. Interestingly, NBAS was also identified as a component of the Syntaxin 18 complex that is localized at the Endoplasmic reticulum (ER) and is required for vesicular trafficking and ER homeostasis. I will discuss current experiments aiming to uncover whether NBAS has two separate functions as an NMD factor and as a component of the ER-Golgi tethering complex or whether these two functions are somehow linked. I will also discuss the functional characterization of an ER-NMD pathway.