|
|
RESEARCH INTERESTS
mRNA Regulation and Stress Responses
ER stress and the Rapid Ire1-Dependent Decay pathway
PUBLICATIONS
mRNA Regulation and Stress Responses
An essential feature of living cells is the ability to adapt quickly to changes in their environment. While transcriptional regulation is often responsible for longer-term changes, altering the stability of an mRNA can alter protein expression quite rapidly. Accordingly, mRNA degradation has been shown to be involved in many important processes, such as cell cycle progression, immune responses, and circadian rhythms. Our overall goal is to understand the mechanisms by which cells control mRNA turnover and the relationships between mRNA stability, localization, and translation.
ER stress and the Rapid Ire1-Dependent Decay pathway
As a postdoc, I found that cells employ mRNA decay in regulating the endoplasmic reticulum (ER), a eukaryotic organelle responsible for the synthesis and folding of secreted and membrane-bound proteins. The ER must process an enormous flux of proteins (up to thousands of proteins per second!) and yet maintain a strict quality control system to ensure that potentially harmful proteins do not traffic to the cell surface. The unfolded protein response (UPR) is a collection of transcriptional and translational mechanisms that allows cells to balance the load of incoming proteins with the folding capacity of the ER. Failure to maintain this balance leads to the accumulation of misfolded proteins in the ER, referred to as ER stress, and can have drastic results- persistent ER stress is linked to several diseases, including diabetes, Alzheimer's disease, and multiple myeloma.
Ire1, a conserved sensor of ER stress, is a transmembrane protein that cleaves the mRNA encoding the transcription factor XBP-1 in response to the accumulation of misfolded proteins in the ER. This leads to the splicing and activation of XBP-1, which in turn helps to transcriptionally remodel the early secretory pathway and increase the folding capacity of the ER. We have found that Ire1 has a surprising alternate function in regulating the degradation of mRNAs localized to the ER membrane. The degradation is rapid compared to the transcriptional responses of the UPR, leading us to name the response Rapid Ire1-Dependent Decay, or RIDD. This pathway is well-suited to solve two problems associated with ER stress. First, it has the potential to immediately relieve the load on the ER, by removing the burden of synthesizing proteins from the target mRNAs. Second, the large-scale transcriptional upregulation of ER components that is initiated by the UPR would initially increase ER stress, as many of the new chaperones and other proteins are synthesized at the ER membrane. The RIDD pathway may therefore function to clear out the translocation and folding machinery, making way for the subsequent influx of proteins directly involved in ER function.
Current projects
1. Mechanism and specificity of the RIDD pathway
There are many physiological and mechanistic aspects of the RIDD pathway that have yet to be explored. For example, Ire1 is thought to have extremely limited substrate specificity, making its involvement in the decay of a broad spectrum of mRNAs is particularly intriguing. Is Ire1 capable of a much more relaxed specificity, or does it activate or recruit another, as of yet unidentified nuclease? Is its specificity regulated? And can the RIDD pathway account for some of the mysteries surrounding Ire1's in vivo effects?
2. Subcellular localization of mRNAs
The signal sequence mechanism for localizing messages encoding secreted proteins has been well-established for more than twenty years. However, it has recently become clear that many mRNAs encoding cytosolic and nuclear proteins are also localized to the ER membrane. How- and perhaps more importantly, why- are these mRNAs targeted to the ER? Although most RIDD targets contain signal sequences that are required for their decay, a few targets appear to encode cytoplasmic or nuclear proteins, thus offering an exciting jumping-off point for understanding the relationship between localization and regulation of mRNAs.
3. Large-scale approaches to studying mRNA stability
We also plan to attack questions of how mRNA turnover is regulated using genome-wide approaches such as microarrays and high-throughput sequencing. We will look for clues to explain how specificity achieved in regulating mRNA stability, how the mRNA quality control machinery chooses targets, and how mRNA stability is modulated under conditions of stress.
Selected Publications
Hollien, J. and Weissman, J.S. 2006. Degradation of endoplasmic reticulum localized mRNAs during the unfolded protein response. Science 313: 104-107.
| |
|
|
