Chemoproteomics reveals Toll-like receptor fatty acylation
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Date
2014
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
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. Spalmitoylation
of TLR2 is a previously unknown immunoregulatory mechanism that represents an entirely novel avenue
for modulation of TLR2 inflammatory activity.
Description
Partial funding for Open Access provided by The Ohio State University Open Access Fund.
Keywords
Citation
Nicholas M. Chesarino, Jocelyn C. Hach, James L. Chen, Balyn W. Zaro, Murugesan VS Rajaram, Joanne Turner, Larry S. Schlesinger, Matthew R. Pratt, Howard C. Hang, and Jacob S. Yount. "Chemoproteomics reveals Toll-like receptor fatty acylation." BMC Biology 2014, 12:91. DOI: 10.1186/s12915-014-0091-3