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BMC Biol. 2014 Nov 5;12:91. doi: 10.1186/s12915-014-0091-3.

Chemoproteomics reveals Toll-like receptor fatty acylation.

Author information

1
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, 43210, USA. Chesarino.1@osu.edu.
2
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, 43210, USA. hach.6@osu.edu.
3
Biomedical Informatics, Internal Medicine in the Division of Medical Oncology, The Ohio State University, Columbus, OH, 43210, USA. James.Chen@osumc.edu.
4
Departments of Chemistry and Molecular and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA. balynzaro@gmail.com.
5
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, 43210, USA. Murugesan.Rajaram@osumc.edu.
6
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, 43210, USA. Joanne.Turner@osumc.edu.
7
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, 43210, USA. larry.schlesinger@osumc.edu.
8
Departments of Chemistry and Molecular and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA. matthew.pratt@usc.edu.
9
Laboratory of Chemical Biology and Microbial Pathogenesis, Rockefeller University, New York, NY, 10065, USA. hhang@rockefeller.edu.
10
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, 43210, USA. yount.37@osu.edu.

Abstract

BACKGROUND:

Palmitoylation 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.

RESULTS:

A 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.

CONCLUSIONS:

This 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.

PMID:
25371237
PMCID:
PMC4240870
DOI:
10.1186/s12915-014-0091-3
[Indexed for MEDLINE]
Free PMC Article

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