Chemoproteomics reveals Toll-like receptor fatty acylation

BMC Biology

Research Article

James L Chen¹  Jocelyn C Hach²  Larry S Schlesinger²  Nicholas M Chesarino²  Murugesan VS Rajaram²  Joanne Turner²  Jacob S Yount²  Balyn W Zaro³  Matthew R Pratt³  Howard C Hang⁴ 

[1] Biomedical Informatics, Internal Medicine in the Division of Medical Oncology, The Ohio State University, 43210, Columbus, OH, USA;Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, 43210, Columbus, OH, USA;Departments of Chemistry and Molecular and Computational Biology, University of Southern California, 90089, Los Angeles, CA, USA;Laboratory of Chemical Biology and Microbial Pathogenesis, Rockefeller University, 10065, New York, NY, USA;

关键词: Palmitoylation;    Post-translational modification;    Click chemistry;    Toll-like receptor;    TLR2;    Fatty acylation;    Proteomics;   

DOI  :  10.1186/s12915-014-0091-3

 received in 2014-08-11, accepted in 2014-10-20,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundPalmitoylation is a 16-carbon lipid post-translational modification that increases protein hydrophobicity. This form of protein fatty acylation is emerging as a critical regulatory modification for multiple aspects of cellular interactions and signaling. Despite recent advances in the development of chemical tools for the rapid identification and visualization of palmitoylated proteins, the palmitoyl proteome has not been fully defined. Here we sought to identify and compare the palmitoylated proteins in murine fibroblasts and dendritic cells.ResultsA total of 563 putative palmitoylation substrates were identified, more than 200 of which have not been previously suggested to be palmitoylated in past proteomic studies. Here we validate the palmitoylation of several new proteins including Toll-like receptors (TLRs) 2, 5 and 10, CD80, CD86, and NEDD4. Palmitoylation of TLR2, which was uniquely identified in dendritic cells, was mapped to a transmembrane domain-proximal cysteine. Inhibition of TLR2 S-palmitoylation pharmacologically or by cysteine mutagenesis led to decreased cell surface expression and a decreased inflammatory response to microbial ligands.ConclusionsThis work identifies many fatty acylated proteins involved in fundamental cellular processes as well as cell type-specific functions, highlighting the value of examining the palmitoyl proteomes of multiple cell types. S-palmitoylation of TLR2 is a previously unknown immunoregulatory mechanism that represents an entirely novel avenue for modulation of TLR2 inflammatory activity.

【 授权许可】

Unknown   
© Chesarino et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.