RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

AC McKelvey, TB Lear, SR Dunn, J Evankovich… - Elife, 2016 - elifesciences.org
Elife, 2016elifesciences.org
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 …
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 of Staphylococcus aureus. There is a negative correlation between PPP1R11 and TLR2 levels in white blood cell samples isolated from patients with Staphylococcus aureus infections. 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.
DOI: http://dx.doi.org/10.7554/eLife.18496.001
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