期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 8, 页码 2186-2202出版社
ELSEVIER
DOI: 10.1074/jbc.RA119.010486
关键词
multifunctional protein; aminoacyl tRNA synthetase; proteolysis; matrix metalloproteinase (MMP); inflammation; toll-like receptor (TLR); macrophage; innate immunity; moonlighting proteins
资金
- Canadian Institutes of Health Research (CIHR) Foundation Grant [FDN-148408]
- CIHR [MOP-111055]
- Canada Foundation for Innovation [31059]
- Michael Smith Foundation for Health Research [IN-NPG-00105]
- University of British Columbia (UBC) 4-year doctoral fellowship
- CIHR Vanier Canada graduate scholarship
- Centre for Blood Research graduate award
- Vancouver Coastal Health Research Institute (VCHRI)-CIHR-UBC MD/Ph.D. studentship
- Australian Early Career Fellowship
- Canadian MSFHR Research Trainee Fellowship
Tyrosyl-tRNA synthetase ligates tyrosine to its cognate tRNA in the cytoplasm, but it can also be secreted through a noncanonical pathway. We found that extracellular tyrosyl-tRNA synthetase (YRS) exhibited proinflammatory activities. In addition to acting as a monocyte/macrophage chemoattractant, YRS initiated signaling through Toll-like receptor 2 (TLR2) resulting in NF-?B activation and release of tumor necrosis factor ? (TNF?) and multiple chemokines, including MIP-1?/?, CXCL8 (IL8), and CXCL1 (KC) from THP1 monocyte and peripheral blood mononuclear cell?derived macrophages. Furthermore, YRS up-regulated matrix metalloproteinase (MMP) activity in a TNF?-dependent manner in M0 macrophages. Because MMPs process a variety of intracellular proteins that also exhibit extracellular moonlighting functions, we profiled 10 MMPs for YRS cleavage and identified 55 cleavage sites by amino-terminal oriented mass spectrometry of substrates (ATOMS) positional proteomics and Edman degradation. Stable proteoforms resulted from cleavages near the start of the YRS C-terminal EMAPII domain. All of the MMPs tested cleaved at ADS(386)?(LYV)-L-387 and VSG(405)?(406)LVQ, generating 43- and 45-kDa fragments. The highest catalytic efficiency for YRS was demonstrated by MMP7, which is highly expressed by monocytes and macrophages, and by neutrophil-specific MMP8. MMP-cleaved YRS enhanced TLR2 signaling, increased TNF? secretion from macrophages, and amplified monocyte/macrophage chemotaxis compared with unprocessed YRS. The cleavage of YRS by MMP8, but not MMP7, was inhibited by tyrosine, a substrate of the YRS aminoacylation reaction. Overall, the proinflammatory activity of YRS is enhanced by MMP cleavage, which we suggest forms a feed-forward mechanism to promote inflammation.
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