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Molecular Regulation of the Stability of SIGIRR in Ubiquitin-Proteasome System
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A2254 - Molecular Regulation of the Stability of SIGIRR in Ubiquitin-Proteasome System
Author Block: L. Li, J. Wei, S. Li, J. Zhao, Y. Zhao; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, United States.
SIGIRR is a critical receptor for anti-inflammatory cytokine IL-37. It mediates inflammation and immune responses through negatively regulation of ILR and TLR signaling. However, the molecular regulation of SIGIRR stability remains unclear. Here we found that the degradation of SIGIRR induced by IL-37 was prevented with a proteasome inhibitor MG-132 in a time dependent manner. The degradation of SIGIRR was enhanced by overexpression of ubiquitin. SIGIRR was ubiquitinated in K48-linked chains and the 163 site of SIGIRR was critical for its stability. Furtherly lung injury mouse models were induced by intra trachea injection LPS for 24h or P. aeruginosa (strain PA103) for 4h. We demonstrate that the expression of SIGIRR was decreased in LPS or PA103 induced mouse lung tissues than that in PBS group. MAPK signaling is an important inflammation pathway. Here we show that overexpression SIGIRR in RAW cells attenuated LPS-induced phosphorylation of JNK and ERK in a time dependent. Our data suggest that SIGIRR degradation is mediated by the ubiquitin-proteasome system and is critical for pulmonary inflammation. In the future, detection the ubiquitin E3 ligases regulating SIGIRR stability might serve as a unique strategy for treatment of pulmonary inflammation.
Author Block: L. Li, J. Wei, S. Li, J. Zhao, Y. Zhao; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, United States.
SIGIRR is a critical receptor for anti-inflammatory cytokine IL-37. It mediates inflammation and immune responses through negatively regulation of ILR and TLR signaling. However, the molecular regulation of SIGIRR stability remains unclear. Here we found that the degradation of SIGIRR induced by IL-37 was prevented with a proteasome inhibitor MG-132 in a time dependent manner. The degradation of SIGIRR was enhanced by overexpression of ubiquitin. SIGIRR was ubiquitinated in K48-linked chains and the 163 site of SIGIRR was critical for its stability. Furtherly lung injury mouse models were induced by intra trachea injection LPS for 24h or P. aeruginosa (strain PA103) for 4h. We demonstrate that the expression of SIGIRR was decreased in LPS or PA103 induced mouse lung tissues than that in PBS group. MAPK signaling is an important inflammation pathway. Here we show that overexpression SIGIRR in RAW cells attenuated LPS-induced phosphorylation of JNK and ERK in a time dependent. Our data suggest that SIGIRR degradation is mediated by the ubiquitin-proteasome system and is critical for pulmonary inflammation. In the future, detection the ubiquitin E3 ligases regulating SIGIRR stability might serve as a unique strategy for treatment of pulmonary inflammation.
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