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  • THZ531 Most studies have been focused on investigating the m

    2018-11-14

    Most studies have been focused on investigating the molecular control of GPCR ubiquitination by identifying the E3 ubiquitin ligase, while the little information is available for deubiquitination of GPCR by deubiqutinating enzymes. Here we report that a deubiquitinating enzyme, USP11, promotes LPA1 stability by reduction of LPA1 ubiquitination, resulting in enhanced LPA-LPA1 signal pathway. USP11 has been known to regulate stability of ALK5 (Al-Salihi et al., 2012) and promyelocytic leukemia protein (Wu et al., 2014). This report reveals a role of USP11 in the regulation of GPCR stability. An important discovery in this study is that a change of association of LPA1 with USP11 to Nedd4L is triggered by ligand binding. The results provide a model for ubiquitination related enzymes regulation of substrate stability by switching their interaction with substrate. It is this switch between deubiquitination enzyme-GPCR to E3 ubiquitin ligase-GPCR which determines the degree of ubiquitination and degradation of GPCR. The serine 319 was identified as the Nedd4L binding site in LPA1, while the USP11 binding site in LPA1 and how ligand treatment shifts the LPA1 binding from USP11 to Nedd4L are still unclear. It is possible that ligand-induced receptor conformational change triggers the receptor binding from its stabilizer (deubiquitinating enzyme) to destabilizer (ubiquitin E3 ligase). USP11 also deubiquitinates SUMO-ubiquitin chains from PML (Wu et al., 2014), while the sumolytion of LPA1 has not been discovered. LPA1 is recognized as pro-inflammatory GPCR in the lung inflammatory diseases (Tager et al., 2008; Zhao et al., THZ531 2011; Zhao et al., 2006). LPA induced cytokine release in lung epithelial THZ531 (Cummings et al., 2004; Zhao et al., 2005; Saatian et al., 2006), leading to recruit neutrophil influx (He et al., 2009). Recent studies have shown that LPA1 interacts with CD14, co-receptor of LPS (Zhao et al., 2011; Zhao et al., 2015). Understanding regulation of LPA1 stability may provide an advanced therapeutic strategy to lessen inflammatory lung diseases by down-regulating, but not completely inhibiting, LPA1 levels. The current study shows that USP11 has pro-inflammatory effect in lung inflammatory injury. This is contrast with the previous finding that USP11 negatively regulates TNFα-induced cytokine release by targeting NF-κB pathway in Hela cells (Sun et al., 2010). The controversial conclusion may be due to using different cell types and stimuli. This study shows that USP11 stabilizes LPA1, thus leading an increase in LPA1-CD14 complex on the cell surface, which contributes LPS-induced signaling and cytokine release in lung epithelial cells. This finding indicates that targeting USP11 attenuates endotoxin-induced inflammatory responses in the murine model of lung injury.
    Conflict of Interest Statement
    Author Contributions
    Acknowledgements We thank Rama Mallampalli and Bill Chen for discussion. This work was supported by the US National Institutes of Health (R01HL131665 and R01HL112791 to Y. Z, R01GM115389 to J.Z.), American Heart Association (12SDG9050005 to J.Z.; 16GRNT30660001 to Y.Z.), and American Lung Association Biomedical Research Grant RG350146 (J.Z.). These funding sources had no role in the study design; in the analysis of data; in the writing of the manuscript; and in the decision to submit the paper for publication.
    Introduction Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination of axons in the central nervous system (CNS). The cells that produce myelin in the CNS, oligodendrocytes (ODCs) (Bunge et al., 1962; Bunge, 1968), die from an autoimmune response that results in demyelinated lesions in the brain and spinal cord (Noseworthy et al., 2000; Olsen and Akirav, 2015). Axonal demyelination reduces the signal strength of nerve impulses (Waxman, 1977; Felts et al., 1997) and may leave the axon exposed to degeneration (Ferguson et al., 1997). Demyelinated lesions can be visualized by magnetic resonance imaging (MRI); however, this procedure is costly and cannot detect diffused or mild myelin degeneration or measure the active loss of ODCs. Although new innovations in MS therapy are currently being explored (Olsen and Akirav, 2015), there are currently no clinically approved molecular biomarkers of ODC death in MS. This unmet need impairs MS diagnosis, prognosis, and assessment of clinical intervention.