Spatiotemporal regulation of ubiquitin-mediated protein degradation via upconversion optogenetic nanosystem
protein degradation, ubiquitin-proteasome system, optogenetics, upconversion materials, the nonstructural protein9 (NSP9), porcine reproductive and respiratory syndrome virus (PRRSV)
Protein degradation technology, which is one of the most direct and effective ways to regulate the life activities of cells, is expected to be applied to the treatment of various diseases. However, current protein degradation technologies such as some small-molecule degraders which are unable to achieve spatiotemporal regulation, making them difficult to transform into clinical applications. In this article, an upconversion optogenetic nanosystem was designed to attain accurate regulation of protein degradation. This system worked via two interconnected parts: 1) the host cell expressed light-sensitive protein that could trigger the ubiquitin-proteasome pathway upon blue-light exposure; 2) the light regulated light-sensitive protein by changing light conditions to achieve regulation of protein degradation. Experimental results based on model protein (Green Fluorescent Protein, GFP) validated that this system could fulfill protein degradation both in vitro (both Hela and 293T cells) and in vivo (by upconversion optogenetic nanosystem), and further demonstrated that we could reach spatiotemporal regulation by changing the illumination time (0-25 h) and the illumination frequency (the illuminating frequency of 0-30 s every 1 min). We further took another functional protein (The Nonstructural Protein 9, NSP9) into experiment. Results confirmed that the proliferation of porcine reproductive and respiratory syndrome virus (PRRSV) was inhibited by degrading the NSP9 in this light-induced system, and PRRSV proliferation was affected by different light conditions (illumination time varies from 0-24 h). We expected this system could provide new perspectives into spatiotemporal regulation of protein degradation and help realize the clinical application transformation for treating diseases of protein degradation technology.
Tsinghua University Press
Yafeng Hao, Taofeng Du, Gaoju Pang, Jiahua Li, Huizhuo Pan, Yingying Zhang, Lizhen Wang, Jin Chang, En-min Zhou, Hanjie Wang. Spatiotemporal regulation of ubiquitin-mediated protein degradation via upconversion optogenetic nanosystem. Nano Research 2020, 13(12): 3253-3260.