2. Academic Validation
  3. Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage

Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage

  • J Biol Chem. 2020 Feb 21;295(8):2186-2202. doi: 10.1074/jbc.RA119.010486.
Parker G Jobin 1,  Nestor Solis 2,  Yoan Machado 2,  Peter A Bell 2,  Simran K Rai 3,  Nam Hoon Kwon 4,  Sunghoon Kim 4,  Christopher M Overall 5,  Georgina S Butler 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
  • 2 Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
  • 3 Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Graduate Program in Bioinformatics, University of British Columbia, Vancouver, British Columbia V5T 4S6, Canada.
  • 4 College of Pharmacy, Seoul National University, 151-742, Seoul, Republic of Korea; Medicinal Bioconvergence Research Center, Seoul National University, 151-742, Seoul, Republic of Korea.
  • 5 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: chris.overall@ubc.ca.
PMID: 31771979 DOI: 10.1074/jbc.RA119.010486
Abstract

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-κB activation and release of tumor necrosis factor α (TNFα) and multiple chemokines, including MIP-1α/β, 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 TNFα-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 ADS386↓387LYV and VSG405↓406LVQ, 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 TNFα 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.

Keywords

aminoacyl tRNA synthetase; inflammation; innate immunity; macrophage; matrix metalloproteinase (MMP); moonlighting proteins; multifunctional protein; proteolysis; toll-like receptor (TLR).

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