Abstract
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.
Highlights
The human toll-like receptor (TLR) family consists of ten family members (TLR1-TLR10) (Chuang and Ulevitch, 2004)
We show a novel mechanism by which the previously unrecognized RING finger E3 ligase, PPP1R11, attenuates Toll-like receptor 2 (TLR2) signaling in response to S. aureus infection by targeting TLR2 for proteasomal degradation
Canonical RING finger domains contain the consensus sequence C-X2-C-X[9-39]-C-X[1-3]-H-X[2-3]-C-X2-C-X[4-48]-C-X2-C, where both cysteine and histidine residues are involved in zinc coordination (Borden and Freemont, 1996)
Summary
The human toll-like receptor (TLR) family consists of ten family members (TLR1-TLR10) (Chuang and Ulevitch, 2004). TLRs are single transmembrane pattern recognition receptors that recognize molecules derived from various pathogens, referred to as pathogen-associated molecular patterns (PAMPs) (Crespo-Lessmann et al, 2010; Delgado et al, 2008; Esen and Kielian, 2006; Chalifour et al, 2004; Tobian et al, 2003). TLRs are highly conserved from invertebrates to mammals, and are essential for mediating innate immunity and the production of cytokines in response to infectious agents (O’Neill, 2000). All TLRs share common structural features, including multiple leucine-rich repeats (LRR), a transmembrane domain, and a conserved cytoplasmic TollÀinterleukin 1 receptor (IL-1R) domain (TIR domain) (Chuang and Ulevitch, 2004). TLR2 is the key element of innate immunity that defends against gram-positive bacteria (Raby et al, 2013).
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