TY - JOUR
T1 - Desuccinylation-Triggered Peptide Self-Assembly: Live Cell Imaging of SIRT5 Activity and Mitochondrial Activity Modulation
AU - Yang, Liu
AU - Peltier, Raoul
AU - Zhang, Manman
AU - Song, Dan
AU - Huang, Hui
AU - Chen, Ganchao
AU - Chen, Ying
AU - Zhou, Fanghang
AU - Hao, Quan
AU - Bian, Liming
AU - He, Ming Liang
AU - Wang, Zuankai
AU - Hu, Yi
AU - Sun, Hongyan
N1 - Funding Information:
We are grateful for the financial support from financial support of the Hong Kong Research Grants Council (Nos. 11102719 and 11304118), National Science Foundation of China (Nos. 21778044, 21572190, and 11875269) and the Science Technology and Innovation Committee of Shenzhen Municipality (JCYJ20180507181654823).
Publisher Copyright:
©
PY - 2020/10/21
Y1 - 2020/10/21
N2 - Mimicking nature's ability to orchestrate molecular self-assembly in living cells is important yet challenging. Molecular self-assembly has found wide applications in cellular activity control, drug delivery, biomarker imaging, etc. Nonetheless, examples of suborganelle-confined supramolecular self-assembly are quite rare and research in this area remains challenging. Herein, we have presented a new strategy to program supramolecular self-assembly specifically in mitochondria by leveraging on a unique enzyme SIRT5. SIRT5 is a mitochondria-localized enzyme belonging to a family of NAD+-dependent histone deacetylases. Accumulating studies suggest that SIRT5 is involved in regulating diverse biological processes, such as reactive oxygen defense, fatty acid metabolism, and apoptosis. In this study, we designed a novel class of succinylated peptide precursors that can be transformed into self-assembling building blocks through SIRT5 catalysis, leading to the formation of supramolecular nanofibers in vitro and in living cells. The increased hydrophobicity arising from self-assembly remarkably enhanced the fluorescence of nitrobenzoxadiazole (NBD) in the nanofibers. With this approach, we have enabled activity-based imaging of SIRT5 in living cells for the first time. Moreover, SIRT5-mediated peptide self-assembly was found to depolarize mitochondria membrane potential and promote ROS formation. Coincubation of the peptide with three different chemotherapeutic agents significantly boosted the anticancer activities of these drugs. Our work has thus illustrated a new way of mitochondria-confined peptide self-assembly for SIRT5 imaging and potential anticancer treatment.
AB - Mimicking nature's ability to orchestrate molecular self-assembly in living cells is important yet challenging. Molecular self-assembly has found wide applications in cellular activity control, drug delivery, biomarker imaging, etc. Nonetheless, examples of suborganelle-confined supramolecular self-assembly are quite rare and research in this area remains challenging. Herein, we have presented a new strategy to program supramolecular self-assembly specifically in mitochondria by leveraging on a unique enzyme SIRT5. SIRT5 is a mitochondria-localized enzyme belonging to a family of NAD+-dependent histone deacetylases. Accumulating studies suggest that SIRT5 is involved in regulating diverse biological processes, such as reactive oxygen defense, fatty acid metabolism, and apoptosis. In this study, we designed a novel class of succinylated peptide precursors that can be transformed into self-assembling building blocks through SIRT5 catalysis, leading to the formation of supramolecular nanofibers in vitro and in living cells. The increased hydrophobicity arising from self-assembly remarkably enhanced the fluorescence of nitrobenzoxadiazole (NBD) in the nanofibers. With this approach, we have enabled activity-based imaging of SIRT5 in living cells for the first time. Moreover, SIRT5-mediated peptide self-assembly was found to depolarize mitochondria membrane potential and promote ROS formation. Coincubation of the peptide with three different chemotherapeutic agents significantly boosted the anticancer activities of these drugs. Our work has thus illustrated a new way of mitochondria-confined peptide self-assembly for SIRT5 imaging and potential anticancer treatment.
UR - http://www.scopus.com/inward/record.url?scp=85094220448&partnerID=8YFLogxK
U2 - 10.1021/jacs.0c08463
DO - 10.1021/jacs.0c08463
M3 - Journal article
C2 - 32991157
AN - SCOPUS:85094220448
SN - 0002-7863
VL - 142
SP - 18150
EP - 18159
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 42
ER -