Stress Response

Eukaryotic cells are highly compartmentalized. Each cell has a nucleus that houses most of our genomic material, and most membrane proteins are synthesized in the endoplasmic reticulum (ER), where these proteins undergo folding and maturation before being trafficked to their ultimate destination. Organelles such as ER can be subject to stress, for example when proteins with structural problems overwhelm its protein folding capacity (e.g. Ryoo et al., 2007; Tien et al., 2008). Most eukaryotic cells can efficiently deal with moderate levels of stress by signaling to the nucleus to induce the expression of quality control genes that help eliminate misfolded proteins in the ER (e.g. Ryoo and Steller, 2007; Malzer et al., 2010).

Chronic ER stress is associated with a wide variety of diseases that plague us. To understand the basis of these diseases, we have been focusing on a fly model for the human disease called Autosomal Dominant Retinitis Pigmentosa. This disease is most frequently caused by mutations in the rhodopsin gene. Interestingly, fruit flies also have rhodopsin-1 mutant alleles that show similar symptoms – retinal degeneration in old individuals. Using genetic and cell biological tools, we had helped establish that these rhodopsin-1 alleles encode proteins that fail to fold properly in the ER. As a result, ER-stress responsive signaling pathway mediated by IRE1 and XBP1 genes are activated in the afflicted fly retina and serve to protect those cells from degeneration (Ryoo et al., 2007). Among the targets of this pathway are proteins that help extract misfolded proteins from the ER for degradation, known as ER-Associated Degradation (ERAD). We showed that Hrd1, a ubiquitin ligase of the ERAD machinery, can strongly delay the course of retinal degeneration in this fly model (Kang and Ryoo, 2009). We believe that our work has therapeutic implications to diseases associated with ER stress.

In addition to the protective branches of ER stress response signaling, we are conducting RNAi screens and gene overexpression studies to find genes that can help cells survive chronic ER stress. Interestingly, we have found a few genes that do not affect known ER quality control pathways, but instead, interfere specifically with the cell death process. Such pathways may serve as potential therapeutic targets for diseases involving proteotoxicity.

Reference:

  1. Ryoo, H.D., Domingos, P., Kang, M.-J., Steller, H. (2007) Unfolded protein response in a Drosophila model for retinal degeneration. EMBO J. 26(1): 242-252.
  2. Ryoo, H.D., Steller, H. (2007) Unfolded protein response in Drosophila: why another model can make it fly. Cell Cycle 6(7): 830-835.
  3. Tien, A.C., Rajan, A., Schulze, K.L., Ryoo, H.D., Acar, M., Steller, H., Bellen, H.J. (2008) Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster. J. Cell Biol. 182(6): 1113-1125.
  4. Kang, M.-J., Ryoo, H.D. (2009) Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation. Proc. Natl. Acad. Sci. USA. 106(40): 17043-17048.
  5. Malzer, E., Daly, M.L., Moloney, A., Sendall, T.J., Thomas, S.E., Ryder, E., Ryoo, H.D., Crowther, D.C., Lomas, D.A., Marciniak, S.J. (2010) Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J. Cell Sci. 123(Pt 17): 2892-2900.