Spatiotemporal regulation of ubiquitin-mediated protein degradation via upconversion optogenetic nanosystem
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Spatiotemporal regulation of ubiquitin-mediated protein degradation via upconversion optogenetic nanosystem Yafeng Hao1,§, Taofeng Du2,§, Gaoju Pang1, Jiahua Li1, Huizhuo Pan1, Yingying Zhang1, Lizhen Wang2, Jin Chang1, En-min Zhou2 (), and Hanjie Wang1 () 1
School of Life Sciences, Tianjin University, Tianjin 300072, China Department of preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China § Yafeng Hao and Taofeng Du contributed equally to this work. 2
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 28 January 2020 / Revised: 17 July 2020 / Accepted: 20 July 2020
ABSTRACT 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 ubiquitinproteasome 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.
KEYWORDS protein degradation, ubiquitin-proteasome system, optogenetics, upconversion materials, the nonstructural protein9 (NSP9), porcine reproductive and respiratory syndrome virus (PRRSV)
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Introduction
Interfering with protein function contributes to treat various diseases caused by abnormal protein expression [1–3]. Among all methods, protein degradation technology as one of the most direct and effective ways to interfere with protein function, could further affect molecular processes [4], cellular signaling [5–7],
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