Xiaoran Guo

All Publications

• The Zn 2+transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila DEVELOPMENTAL CELL Guo, X., Mutch, M., Torres, A., Nano, M., Rauth, N., Harwood, J., McDonald, D., Chen, Z., Montell, C., Dai, W., Montell, D. J. 2024; 59 (13): 1655-1667.e6

  Abstract

  Proteotoxic stress drives numerous degenerative diseases. Cells initially adapt to misfolded proteins by activating the unfolded protein response (UPR), including endoplasmic-reticulum-associated protein degradation (ERAD). However, persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. The ER-localized Zn2+ transporter ZIP7 is conserved from plants to humans and required for intestinal self-renewal, Notch signaling, cell motility, and survival. However, a unifying mechanism underlying these diverse phenotypes was unknown. In studying Drosophila border cell migration, we discovered that ZIP7-mediated Zn2+ transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn2+ metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn2+ are limiting for deubiquitination. In a Drosophila model of neurodegeneration caused by misfolded rhodopsin (Rh1), ZIP7 overexpression degrades misfolded Rh1 and rescues photoreceptor viability and fly vision. Thus, ZIP7-mediated Zn2+ transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.

  View details for DOI 10.1016/j.devcel.2024.04.003

  View details for Web of Science ID 001267839300001

  View details for PubMedID 38670102

  View details for PubMedCentralID PMC11233247

• Tissue topography steers migrating Drosophila border cells. Science (New York, N.Y.) Dai, W., Guo, X., Cao, Y., Mondo, J. A., Campanale, J. P., Montell, B. J., Burrous, H., Streichan, S., Gov, N., Rappel, W. J., Montell, D. J. 2020; 370 (6519): 987-990

  Abstract

  Moving cells can sense and respond to physical features of the microenvironment; however, in vivo, the significance of tissue topography is mostly unknown. Here, we used Drosophila border cells, an established model for in vivo cell migration, to study how chemical and physical information influences path selection. Although chemical cues were thought to be sufficient, live imaging, genetics, modeling, and simulations show that microtopography is also important. Chemoattractants promote predominantly posterior movement, whereas tissue architecture presents orthogonal information, a path of least resistance concentrated near the center of the egg chamber. E-cadherin supplies a permissive haptotactic cue. Our results provide insight into how cells integrate and prioritize topographical, adhesive, and chemoattractant cues to choose one path among many.

  View details for DOI 10.1126/science.aaz4741

  View details for PubMedID 33214282

  View details for PubMedCentralID PMC8103818

• Akt1 and dCIZ1 promote cell survival from apoptotic caspase activation during regeneration and oncogenic overgrowth. Nature communications Sun, G., Ding, X. A., Argaw, Y., Guo, X., Montell, D. J. 2020; 11 (1): 5726

  Abstract

  Apoptosis is an ancient and evolutionarily conserved cell suicide program. During apoptosis, executioner caspase enzyme activation has been considered a point of no return. However, emerging evidence suggests that some cells can survive caspase activation following exposure to apoptosis-inducing stresses, raising questions as to the physiological significance and underlying molecular mechanisms of this unexpected phenomenon. Here, we show that, following severe tissue injury, Drosophila wing disc cells that survive executioner caspase activation contribute to tissue regeneration. Through RNAi screening, we identify akt1 and a previously uncharacterized Drosophila gene CG8108, which is homologous to the human gene CIZ1, as essential for survival from the executioner caspase activation. We also show that cells expressing activated oncogenes experience apoptotic caspase activation, and that Akt1 and dCIZ1 are required for their survival and overgrowth. Thus, survival following executioner caspase activation is a normal tissue repair mechanism usurped to promote oncogene-driven overgrowth.

  View details for DOI 10.1038/s41467-020-19068-2

  View details for PubMedID 33184261

  View details for PubMedCentralID PMC7664998