Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury

Abstract

Lysophosphatidic acid receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated cytokine release. The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis-association with USP11 and in turn binding to Nedd4L. Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS-induced inflammatory responses and lung injury in preclinical murine models. Thus, our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides potential targets for the development of anti-inflammatory molecules to lessen lung injury.

Regulation of the ubiquitylation and deubiquitylation of CREB-binding protein modulates histone acetylation and lung inflammation

“…FBXL19 is a subunit of an SCF family E3 ubiquitin ligase, which exhibits an anti-inflammatory property (23); however, its substrates related to cytokine gene expression have not been identified. We tested whether FBXL19 regulated the protein stability of HATs.…”

“…S4A). We previously showed that the phosphorylation of substrates promotes their binding to E3 ubiquitin ligases (23). Thus, the phosphorylation of CBP may inhibit its interaction with FBXL19.…”

Oligonucleotide Therapies for the Lung: Ready to Return to the Clinic?

“…After all, the TLR4 agonist lipopolysaccharide (LPS) is a well-established tool for the induction of mucous hypersecretion as well as the host of associated osmoregulatory gene expression changes reported in the proposed Nedd4L ASO CF model. 17 Thus, as with previous efforts, interpretation of the reported data as a mechanistically-relevant, on target, and effective treatment of CF might be premature.…”

The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…After their receptor activation, cIAP-mediated K63-ubiquitination of RIPK1 and the TRAF proteins leads to the recruitment of linear ubiquitin chain assembly complex (LUBAC). The stability of lysophosphatidic acid receptor 1 (LPA1) is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated proinflammatory effects [33,[36][37][38][39]. Furthermore, the deubiquitinating enzyme USP13 stabilizes the anti-inflammatory receptor IL-1R8/Sigirr to suppress lung inflammation [40][41][42].…”

“…NLRP3 [38] Regulates NLRP3 inflammasome activation [38] NF-κB [39], NEMO [33] Regulates NF-κB signaling [33,39] VP24 [49] Involves in virus replication [49] Tat [50] Involves in virus production [50] TRAF3/TRAF6 [51] Modulates antiviral signaling [51] TRAF6/IKKγ [34] Regulates TLR signaling [34] USP-10 CFTR [37,52] Epithelial mucosal clearance [37,52] NICD1 [53] Regulates Notch signaling [53] USP-11 E2F1 [54] Regulates lung epithelia proliferation and wound healing [54] LPA1 [36] Enhances inflammation [36] USP-13 IL-1R8/Sigirr [40] Suppresses lung inflammation [40] PTEN [41] Regulates cell apoptosis [41] MCL1 [42] Regulates transformation of fibroblasts [42] STAT1 [55] Regulates IFN Signaling [55] STING [56] Negatively regulates antiviral responses [56] USP-14 I-kB [31] Increases cytokine release [31] CBP [32] Lung inflammation [32] USP-15 IκBα [57] NF-κB activation [57] USP-17 HDAC2 [58] Reverses glucocorticoid resistance [58] TRAF2/TRAF3 [59] Lung inflammation [59] [92] Inhibits type I IFN signaling and antiviral response [92] POH1 pro-IL-1β [93] Negatively regulates the immune response [93] BRCC3 NLRP3…”