PTPN14 aggravates inflammation through promoting proteasomal degradation of SOCS7 in acute liver failure.
PTPN14 aggravates inflammation through promoting proteasomal degradation of SOCS7 in acute liver failure.
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PTPN14通过促进急性肝衰竭中SOCS7的蛋白酶体降解而加重炎症
DOI：
10.1038/s41419-020-03014-7
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发表时间：
2020-09-25
影响因子：
9
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Fu B;Yin S;Lin X;Shi L;Wang Y;Zhang S;Zhao Q;Li Z;Yang Y;Wu H
急性肝衰竭（ALF）是一种罕见但危及生命的全身性疾病。天然免疫调节在此过程中发挥着重要作用；但具体机制尚不完全清楚。利用LPS + D-GalN诱导的ALF小鼠模型，我们发现PTPN14缺陷小鼠的存活率高于对照组，而炎症因子的释放明显较低。我们进一步发现PTPN14与SOCS7相互作用，并通过K11和K48处的泛素化促进SOCS7的降解，从而降低SOCS7的蛋白水平，减弱对炎症因子的抑制作用。更重要的是，SOCS7通过阻止IKK复合物的活性来阻断NF-κB信号通路，进而减少下游炎症因子的表达。本研究首次在ALF小鼠模型中报道了SOCS7对NF-κB通路的抑制作用，并阐明了PTPN14-SOCS7-NF-κB轴调节炎症的机制。这些结果为ALF的临床治疗提供了新的见解。
Acute liver failure (ALF) is a rare but life-threatening systemic disorder. The innate immune regulation has an important role in this process; however, the specific mechanisms are not completely clear. Using the LPS + D-GalN-induced ALF mouse model, we found that the survival rate of PTPN14-deficient mice was higher than that of the control group, while the release of inflammatory factors was significantly lower. We further showed that PTPN14 interacted with SOCS7, and promoted the degradation of SOCS7 through ubiquitination at K11 and K48, thereby reducing the protein level of SOCS7 and weakening the inhibitory effects on inflammatory factors. More importantly, SOCS7 blocked the NF-κB signaling pathway by preventing the activity of the IKK complex, and then reduced the expression of downstream inflammatory factors. In this study, we firstly reported the inhibitory effect of SOCS7 on the NF-κB pathway in the ALF mouse model and elucidated the mechanism of PTPN14–SOCS7–NF-κB axis in the regulation of inflammation. These results provide new insights into the clinical treatment of ALF.
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影响因子：
50.3
作者：
Mello SS;Valente LJ;Raj N;Seoane JA;Flowers BM;McClendon J;Bieging-Rolett KT;Lee J;Ivanochko D;Kozak MM;Chang DT;Longacre TA;Koong AC;Arrowsmith CH;Kim SK;Vogel H;Wood LD;Hruban RH;Curtis C;Attardi LD
通讯作者：
Attardi LD
影响因子：
44.1
作者：
Swatek KN;Komander D
通讯作者：
Komander D
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影响因子：
6.4
作者：
Fu, Beibei;Xue, Weiwei;Wu, Haibo
通讯作者：
Wu, Haibo
影响因子：
4.3
作者：
Qin CC;Liu YN;Hu Y;Yang Y;Chen Z
通讯作者：
Chen Z
影响因子：
5.2
作者：
Duncan SA;Baganizi DR;Sahu R;Singh SR;Dennis VA
通讯作者：
Dennis VA