Associate Professor of Biological Sciences
B.A. Reed College
Ph.D. University of California, Berkeley
Julie Hollien's Lab Page
Julie Hollien's PubMed Literature Search
Molecular Biology Program
Endoplasmic Reticulum (ER) Stress
ER stress and the Unfolded Protein Response
The endoplasmic reticulum (ER) is responsible for the synthesis and folding of secreted and membrane-bound proteins. It must process a sometimes enormous flux of proteins on demand (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. This balance between the load of incoming proteins and the folding capacity of the ER is maintained by a collection of transcriptional and translational mechanisms termed the Unfolded Protein Response, or UPR. 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.
Regulated Ire1-Dependent Decay (RIDD)
Ire1, a conserved sensor of ER stress, is a transmembrane protein that cleaves the mRNA encoding the transcription factor Xbp1 in response to the accumulation of misfolded proteins in the ER. This leads to the splicing and activation of Xbp1, which in turn helps to transcriptionally remodel the early secretory pathway and increase the folding capacity of the ER. We have found that Ire1 also degrades other mRNAs localized to the ER membrane, a pathway we call Regulated Ire1-Dependent Decay, or RIDD.
In fly cells, the RIDD pathway has a very broad specificity, degrading almost every mRNA that associates with the ER membrane. Because of this, RIDD in fly cells is well-suited to immediately relieve the load on the ER, by removing the burden of synthesizing proteins from the target mRNAs. In mammalian cells, however, the RIDD pathway is much more specific, degrading a handful of mRNAs that contain specific targeting features. We are currently exploring why these particular mRNAs are degraded, and the impact of this pathway on the cell biological effects of ER stress.
The UPR and carbon metabolism
In addition to regulating genes involved in protein folding and trafficking, we have found that the UPR triggers a coordinated change in the expression of metabolic genes. In flies, this leads to a shift to aerobic glycolysis, where cells upregulate glycolysis and down-regulate oxidative phosphorylation (OXPHOS). This shift is also a hallmark of cancer, and certain types of stem cells and immune cells. We are currently examining the mechanism and effects of this metabolic regulation.
- Lee JE, Morrison W, Hollien J. Hairy and enhancer of split 1 (HES1) protects cells from endoplasmic reticulum stress-induced apoptosis through repression of GADD34. Journal of Biological Chemistry (2018) 293(16):5947-5955.
- Nelson J, Moore KA, Chapin A, Hollien J, Metzstein MM. Degradation of Gadd45 mRNA by nonsense-mediated decay is essential for viability. eLife (2016). 10.7554
- Moore K, Hollien J. Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status, Mol Biol Cell (2015) Jun 24. pii: mbc.E15-02-0074. [Epub ahead of print]
- Lee JE, Oney M, Frizzell K, Phadnis N, Hollien J. Drosophila melanogaster activating transcription factor 4 regulates glycolysis during endoplasmic reticulum stress, G3 (Bethesda) 5 (2015) 667-75.
- Sharma AK, Plant JJ, Rangel AE, Meek KN, Anamisis AJ, Hollien J, Heemstra JM. Fluorescent RNA Labeling Using Self-Alkylating Ribozymes, ACS Chem Biol 9 (2014) 1680-4.
- Chapin A, Hu H, Rynearson SG, Hollien J, Yandell M, Metzstein MM. In vivo determination of direct targets of the nonsense-mediated decay pathway in Drosophila, G3 (Bethesda) 4 (2014) 485-96.
- Moore KA, Plant JJ, Gaddam D, Craft J, Hollien J. Regulation of sumo mRNA during endoplasmic reticulum stress, PLoS One 8 (2013) e75723.
- Hollien J. Evolution of the unfolded protein response, Biochim Biophys Acta 1833 (2013) 2458-63.
- Weil D, Hollien J. Cytoplasmic organelles on the road to mRNA decay, Biochim Biophys Acta 1829 (2013) 725-31.
- Gaddam D, Stevens N, Hollien J. Comparison of mRNA localization and regulation during endoplasmic reticulum stress in Drosophila cells, Mol Biol Cell 24 (2013) 14-20.
- Moore KA, Hollien J. The unfolded protein response in secretory cell function, Annu Rev Genet 46 (2012) 165-83.
- Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells, J Cell Biol 186 (2009) 323-331.
- Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response, Science 313 (2006) 104-107.