RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity.
Toll-like receptor 2 (TLR2) is a pattern recognition receptor that recognizes many types of PAMPs that originate from gram-positive bacteria. Here we describe a novel mechanism regulating TLR2 protein expression and subsequent cytokine release through the ubiquitination and degradation of the receptor in response to ligand stimulation. We show a new mechanism in which an uncharacterized RING finger E3 ligase, PPP1R11, directly ubiquitinates TLR2 both in vitro and in vivo, which leads to TLR2 degradation and disruption of the signaling cascade. Lentiviral gene transfer or knockdown of PPP1R11 in mouse lungs significantly affects lung inflammation and the clearance ofStaphylococcus aureus. There is a negative correlation between PPP1R11 and TLR2 levels in white blood cell samples isolated from patients withStaphylococcus aureusinfections. These results suggest that PPP1R11 plays an important role in regulating innate immunity and gram-positive bacterial clearance by functioning, in part, through the ubiquitination and degradation of TLR2.
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
Alison C
AC
McKelvey
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.|Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, United States.|School of Public Health, University of Pittsburgh, Pittsburgh, United States.
Travis B
0000-0001-9156-0844
TB
Lear
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
Sarah R
SR
Dunn
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
John
J
Evankovich
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
James D
JD
Londino
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
Joseph S
JS
Bednash
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
Yingze
Y
Zhang
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
Bryan J
0000-0002-1175-4874
BJ
McVerry
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.
Yuan
Y
Liu
Department of Medicine, University of Pittsburgh, Pittsburgh, United States.|Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, United States.|Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, United States.
Bill B
0000-0003-2695-5107
BB
Chen
D000818:Animals; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D059748:Proteolysis; D013203:Staphylococcal Infections / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000472:pathogenicity; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000276:immunology; D044767:Ubiquitin-Protein Ligases
D047908:Intracellular Signaling Peptides and Proteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C116196:PPP1R11 protein, human; D044767:Ubiquitin-Protein Ligases
ARDS; E3 ligase; TLR2; biochemistry; human; immunology; innate immunity; mouse; ubiquitination; virus