@article{6b240054595741e4b84a8df5d016e772,
title = "Site-Specific Photo-Crosslinking Proteomics Reveal Regulation of IFITM3 Trafficking and Turnover by VCP/p97 ATPase",
abstract = "Interferon-induced transmembrane protein 3 (IFITM3) is a key interferon effector that broadly prevents infection by diverse viruses. However, the cellular factors that control IFITM3 homeostasis and antiviral activity have not been fully elucidated. Using site-specific photo-crosslinking and quantitative proteomic analysis, here we present the identification and functional characterization of VCP/p97 AAA-ATPase as a primary interaction partner of IFITM3. We show that IFITM3 ubiquitination at lysine 24 is crucial for VCP binding, trafficking, turnover, and engagement with incoming virus particles. Consistently, pharmacological inhibition of VCP/p97 ATPase activity leads to defective IFITM3 lysosomal sorting, turnover, and co-trafficking with virus particles. Our results showcase the utility of site-specific protein photo-crosslinking in mammalian cells and reveal VCP/p97 as a key cellular factor involved in IFITM3 trafficking and homeostasis.",
keywords = "IFITM3, VCP/p97, chemical proteomics, photo-crosslinking, protein-protein interaction, unnatural amino acid",
author = "Xiaojun Wu and Spence, {Jennifer S.} and Tandrila Das and Xiaoqiu Yuan and Chengjie Chen and Yuqing Zhang and Yumeng Li and Yanan Sun and Kartik Chandran and Hang, {Howard C.} and Tao Peng",
note = "Funding Information: We thank Prof. Peng R. Chen at Peking University for the pCMV-DiZPK-PylRS plasmid. We also thank the Proteomics Resource Center at The Rockefeller University for assistance in proteomic analysis. T.D. and X.Y. acknowledge the Tri-Institutional Program in Chemical Biology at The Rockefeller University. K.C. acknowledges support from NIH-NIAID R01AI134824. H.C.H. acknowledges support from NIH-NIGMS R01M087544. T.P. acknowledges support from National Natural Science Foundation of China (21778010), Shenzhen Science and Technology Innovation Committee (JCYJ20170412150832022), and Shenzhen Peacock Plan (KQTD2015032709315529). H.C.H. and T.P. conceived and supervised the study. T.P. X.W. J.S.S. and T.D. performed the experiments. X.Y. C.C. Y.Z. Y.L. and Y.S. generated reagents. X.W. J.S.S. T.D. K.C. H.C.H. and T.P. interpreted the data. H.C.H. and T.P. wrote the manuscript with input from all authors. The authors declare no competing interests. Funding Information: We thank Prof. Peng R. Chen at Peking University for the pCMV-DiZPK-PylRS plasmid. We also thank the Proteomics Resource Center at The Rockefeller University for assistance in proteomic analysis. T.D. and X.Y. acknowledge the Tri-Institutional Program in Chemical Biology at The Rockefeller University. K.C. acknowledges support from NIH -NIAID R01AI134824 . H.C.H. acknowledges support from NIH -NIGMS R01M087544 . T.P. acknowledges support from National Natural Science Foundation of China ( 21778010 ), Shenzhen Science and Technology Innovation Committee ( JCYJ20170412150832022 ), and Shenzhen Peacock Plan ( KQTD2015032709315529 ). Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = may,
day = "21",
doi = "10.1016/j.chembiol.2020.03.004",
language = "English (US)",
volume = "27",
pages = "571--585.e6",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "5",
}