The interaction of S100A16 and GRP78 actives endoplasmic reticulum stress-mediated through the IRE1α/XBP1 pathway in renal tubulointerstitial fibrosis.
The interaction of S100A16 and GRP78 actives endoplasmic reticulum stress-mediated through the IRE1α/XBP1 pathway in renal tubulointerstitial fibrosis.
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S100A16 和 GRP78 的相互作用通过 IRE1α/XBP1 通路激活内质网应激介导的肾小管间质纤维化
DOI：
10.1038/s41419-021-04249-8
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发表时间：
2021-10-13
影响因子：
9
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Jin R;Zhao A;Han S;Zhang D;Sun H;Li M;Su D;Liang X
最近的研究表明，急性和慢性肾脏疾病，包括肾纤维化的发展与内质网（ER）应激有关。S100钙结合蛋白16（S100 A16）作为S100家族的新成员参与肾脏疾病的发生，然而，很少有研究探讨S100 A16与内质网应激之间的关系。在我们之前的研究中，我们在HK-2细胞中鉴定了GRP 78作为S100 A16的蛋白伴侣。在此，我们证实了GRP 78和S100 A16在HK-2细胞中的物理相互作用，以及GRP 78在单侧输尿管闭塞小鼠肾脏中的表达显著增加。通过用Lenti-S100 A16感染在HK-2细胞中S100 A16过表达也诱导ER应激标志物的上调，包括GRP 78、p-IRE 1 α和XBP 1 s。免疫荧光染色显示S100 A16与GRP 78的相互作用主要发生在对照HK-2细胞的内质网中。相反，过度表达S100 A16的HK-2细胞显示S100 A16和GRP 78主要在细胞质中共定位。用钙离子螯合剂BAPTA-AM预处理，减弱了HK-2细胞中S100 A16过表达诱导的肾纤维化基因和ER应激标志物的上调，并抑制了GRP 78和S100 A16的胞质共定位。免疫共沉淀研究表明，S100 A16和IRE 1 α在HK-2细胞中与GRP 78存在竞争性结合。总之，我们的研究结果表明，肾损伤后细胞质中S100 A16的表达显著增加。然后，GRP 78进入细胞质并与S100 A16结合以促进IRE 1 α的释放。随后IRE 1 α的磷酸化导致XBP 1剪接，激活ER应激。
Recent studies have indicated that the development of acute and chronic kidney disease including renal fibrosis is associated with endoplasmic reticulum (ER) stress. S100 calcium-binding protein 16 (S100A16) as a novel member of the S100 family is involved in kidney disease; however, few studies have examined fibrotic kidneys for a relationship between S100A16 and ER stress. In our previous study, we identified GRP78 as a protein partner of S100A16 in HK-2 cells. Here, we confirmed a physical interaction between GRP78 and S100A16 in HK-2 cells and a markedly increased expression of GRP78 in the kidneys of unilateral ureteral occlusion mice. S100A16 overexpression in HK-2 cells by infection with Lenti-S100A16 also induced upregulation of ER stress markers, including GRP78, p-IRE1α, and XBP1s. Immunofluorescence staining demonstrated that the interaction between S100A16 and GRP78 predominantly occurred in the ER of control HK-2 cells. By contrast, HK-2 cells overexpressing S100A16 showed colocalization of S100A16 and GRP78 mainly in the cytoplasm. Pretreatment with BAPTA-AM, a calcium chelator, blunted the upregulation of renal fibrosis genes and ER stress markers induced by S100A16 overexpression in HK-2 cells and suppressed the cytoplasmic colocalization of GRP78 and S100A16. Co-immunoprecipitation studies suggested a competitive binding between S100A16 and IRE1α with GRP78 in HK-2 cells. Taken together, our findings demonstrate a significant increase in S100A16 expression in the cytoplasm following renal injury. GRP78 then moves into the cytoplasm and binds with S100A16 to promote the release of IRE1α. The subsequent phosphorylation of IRE1α then leads to XBP1 splicing that activates ER stress.
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影响因子：
4.8
作者：
Wang, Hao;Sun, Ruo-Qiong;Ye, Ji-Ming
通讯作者：
Ye, Ji-Ming
影响因子：
3.1
作者：
Lv H;Hou H;Lei H;Nie C;Chen B;Bie L;Han L;Chen X
通讯作者：
Chen X
影响因子：
4.8
作者：
Sturchler, Emmanuel;Cox, Jos A.;Heizmann, Claus W.
通讯作者：
Heizmann, Claus W.
DOI：
10.13294/j.aps.2019.0027
发表时间：
2019-04-01
期刊：
Shengli Xuebao
影响因子：
--
作者：
Kan Jing-Bao;Shen Ge-Qian;Liu Yun
通讯作者：
Liu Yun
内质网应激在人类病理学中的作用。
DOI：
10.1146/annurev-pathol-012513-104649
发表时间：
2015
期刊：
Annual review of pathology
影响因子：
--
作者：
Oakes SA;Papa FR
通讯作者：
Papa FR