2. Academic Validation
  3. Matrix metalloproteinases inactivate the proinflammatory functions of secreted moonlighting tryptophanyl-tRNA synthetase

Matrix metalloproteinases inactivate the proinflammatory functions of secreted moonlighting tryptophanyl-tRNA synthetase

  • J Biol Chem. 2019 Aug 30;294(35):12866-12879. doi: 10.1074/jbc.RA119.009584.
Parker G Jobin 1,  Nestor Solis 2,  Yoan Machado 2,  Peter A Bell 2,  Nam Hoon Kwon 3,  Sunghoon Kim 3,  Christopher M Overall 4,  Georgina S Butler 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
  • 2 Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Department of Oral Biological and Medical Sciences, University of British Columbia, 2199 Wesbrook Mall, Faculty of Dentistry, Vancouver, British Columbia V6T 1Z3, Canada.
  • 3 College of Pharmacy, Seoul National University, 151-742 Seoul, Republic of Korea; Medicinal Bioconvergance Research Center, Seoul National University, 151-742 Seoul, Republic of Korea.
  • 4 Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Department of Oral Biological and Medical Sciences, University of British Columbia, 2199 Wesbrook Mall, Faculty of Dentistry, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: chris.overall@ubc.ca.
PMID: 31324718 DOI: 10.1074/jbc.RA119.009584
Abstract

Tryptophanyl-tRNA synthetase (WRS) is a cytosolic Aminoacyl-tRNA Synthetase essential for protein synthesis. WRS is also one of a growing number of intracellular proteins that are attributed distinct noncanonical "moonlighting" functions in the extracellular milieu. Moonlighting aminoacyl-tRNA synthetases regulate processes such as inflammation, but how these multifunctional Enzymes are themselves regulated remains unclear. Here, we demonstrate that WRS is secreted from human macrophages, fibroblasts, and endothelial cells in response to the proinflammatory cytokine interferon γ (IFNγ). WRS signaled primarily through Toll-like Receptor 2 (TLR2) in macrophages, leading to phosphorylation of the p65 subunit of NF-κB with associated loss of NF-κB Inhibitor α (IκB-α) protein. This signaling initiated secretion of tumor necrosis factor α (TNFα) and CXCL8 (IL8) from macrophages. We also demonstrated that WRS is a potent monocyte chemoattractant. Of note, WRS increased matrix metalloproteinase (MMP) activity in the conditioned medium of macrophages in a TNFα-dependent manner. Using purified recombinant proteins and LC-MS/MS to identify proteolytic cleavage sites, we demonstrated that multiple MMPs, but primarily macrophage MMP7 and neutrophil MMP8, cleave secreted WRS at several sites. Loss of the WHEP domain following cleavage at Met48 generated a WRS proteoform that also results from alternative splicing, designated Δ1-47 WRS. The MMP-cleaved WRS lacked TLR signaling and proinflammatory activities. Thus, our results suggest that moonlighting WRS promotes IFNγ proinflammatory activities, and these responses can be dampened by MMPs.

Keywords

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

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z