Isoform- and Cell Type-Specific Roles of Glycogen Synthase Kinase 3 N-Terminal Serine Phosphorylation in Liver Ischemia Reperfusion Injury.
Isoform- and Cell Type-Specific Roles of Glycogen Synthase Kinase 3 N-Terminal Serine Phosphorylation in Liver Ischemia Reperfusion Injury.
复制标题
糖原合成酶激酶 3 N 端丝氨酸磷酸化在肝缺血再灌注损伤中的亚型和细胞类型特异性作用
DOI：
10.4049/jimmunol.2000397
复制
发表时间：
2020-08-15
期刊：
影响因子：
--
通讯作者：
Zhai Y
中科院分区：
文献类型：
--
作者：
Ni M;Zhou H;Zhang J;Jin D;Lu T;Busuttil RW;Kupiec-Weglinski JW;Wang X;Zhai Y
糖原合成酶激酶3 (Gsk3) α和β在n端丝氨酸磷酸化刺激下均具有组成性活性和抑制活性。虽然活性Gsk3在肝脏缺血再灌注损伤（IRI）中的作用已经得到了很好的认识，但Gsk3 n端丝氨酸磷酸化是否在疾病过程中具有任何功能意义尚不清楚。在小鼠肝脏局部热缺血模型中，我们研究了gsk3 - n -末端丝氨酸突变敲入（KI）小鼠，发现Gsk3αS21A突变体KI小鼠的肝脏IRI降低，而Gsk3βS9A突变体KI小鼠的肝脏IRI升高。骨髓嵌合实验显示，肝实质中的Gsk3α（而非β）突变可以保护IRI，而骨髓源性细胞中的这两种突变都加重了肝损伤。在机制上，突变体Gsk3α通过激活HIV-1 tat相互作用蛋白60 （TIP60）介导的自噬途径保护肝细胞免受炎症（TNF-α）细胞死亡。药物抑制TIP60或自噬降低了Gsk3α突变体肝细胞对体外炎症细胞死亡和Gsk3α突变体KI小鼠对体内肝脏IR损伤的保护作用。因此，Gsk3 n端丝氨酸磷酸化抑制肝脏先天免疫激活，但在炎症反应中抑制肝细胞自噬。Gsk3 αS21突变，而不是βS9突变，足以维持Gsk4在肝细胞中的活性，并通过TIP60激活保护肝脏免受IRI。
Glycogen synthase kinase 3 (Gsk3) α and β are both constitutively active and inhibited upon stimulation by N-terminal serine phosphorylation. Although roles of active Gsk3 in liver ischemia reperfusion injury (IRI) have been well appreciated, whether Gsk3 N-terminal serine phosphorylation has any functional significance in the disease process remains unclear. In a murine liver partial warm ischemia model, we studied Gsk3-N-terminal serine mutant knock-in (KI) mice and showed that liver IRI was decreased in Gsk3αS21A, but increased in Gsk3βS9A, mutant KI mice. Bone marrow chimeric experiments revealed that the Gsk3α, but not β, mutation in liver parenchyma protected from IRI and both mutations in bone marrow-derived cells exacerbated liver injuries. Mechanistically, mutant Gsk3α protected hepatocytes from inflammatory (TNF-α) cell death by the activation of HIV-1 TAT-interactive protein 60 (TIP60)-mediated autophagy pathway. The pharmacological inhibition of TIP60 or autophagy diminished the protection of the Gsk3α mutant hepatocytes from inflammatory cell death in vitro and the Gsk3α mutant KI mice from liver IR injury in vivo. Thus, Gsk3 N-terminal serine phosphorylation inhibits liver innate immune activation but suppresses hepatocyte autophagy in response to inflammation. Gsk3 αS21, but not βS9, mutation is sufficient to sustain Gsk4 activities in hepatocytes and protect livers from IRI via TIP60 activation.
登录
查看更多内容
影响因子：
13.5
作者：
Gao, Rachel Y.;Wang, Meng;Ju, Cynthia
通讯作者：
Ju, Cynthia
影响因子：
29.4
作者：
Hart, Melanie L.;Much, Chressen;Eltzschig, Holger K.
通讯作者：
Eltzschig, Holger K.
影响因子：
25.7
作者：
Fu, Hailong;Xu, Haitao;Shi, Xueyin
通讯作者：
Shi, Xueyin
影响因子：
15.9
作者：
COLLETTI, LM;REMICK, DG;CAMPBELL, DA
通讯作者：
CAMPBELL, DA
影响因子：
5.3
作者：
Fluegel, Daniela;Goerlach, Agnes;Kietzmann, Thomas
通讯作者：
Kietzmann, Thomas