Regulation of the p38-MAPK pathway by hyperosmolarity and by WNK kinases.
Regulation of the p38-MAPK pathway by hyperosmolarity and by WNK kinases.
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DOI：
10.1038/s41598-022-18630-w
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发表时间：
2022-08-25
影响因子：
4.6
通讯作者：
Rotin, Daniela
中科院分区：
文献类型：
--
作者：
Liu, Zetao;Demian, Wael;Persaud, Avinash;Jiang, Chong;Subramanaya, Arohan R.;Rotin, Daniela
p38-MAPK是由高渗激活的应激反应激酶。在这里，我们询问了相关的途径。我们表明，p38-MAPK信号被激活的高渗刺激在各种解决方案，细胞类型和结肠类器官。在p38-MAPK的上游激活剂TRAF 2/ASK 1（但不是Rac 1）和MKK 3/6/4的水平上检测到高渗透压感知。虽然WNK激酶是已知的MAPK-传感器，但我们意外地发现，WNK（用WNK 463）的短（2小时）抑制导致高渗下p38-MAPK活性升高，这是由WNK 463依赖性刺激MKK 3/6/4的上游激活剂TAK 1或TRAF 2/ASK 1介导的。然而，这种效应是暂时的，并且通过与WNK 463长期（2天）孵育而逆转。因此，抑制p38-MAPK或其上游激活剂ASK 1或TAK 1或WNK 2天（而不是2小时），降低了高渗下细胞收缩后的调节体积增加（RVI）。我们还表明，由离子转运蛋白NKCC 1介导的RVI依赖于p38-MAPK。由于WNK是已知的NKCC 1激活剂，我们提出了控制RVI的WNK- > NKCC 1- > p38-MAPK通路。这一途径由NHE 1增强。此外，高渗抑制mTORC 1激活和细胞增殖。因此，p38-MAPK和WNK的活化对于RVI和细胞增殖是重要的。
p38-MAPK is a stress-response kinase activated by hyperosmolarity. Here we interrogated the pathways involved. We show that p38-MAPK signaling is activated by hyperosmotic stimulation in various solutions, cell types and colonic organoids. Hyperosmolarity sensing is detected at the level of the upstream activators of p38-MAPK: TRAF2/ASK1 (but not Rac1) and MKK3/6/4. While WNK kinases are known osmo-sensors, we found, unexpectedly, that short (2 h) inhibition of WNKs (with WNK463) led to elevated p38-MAPK activity under hyperosmolarity, which was mediated by WNK463-dependent stimulation of TAK1 or TRAF2/ASK1, the upstream activators of MKK3/6/4. However, this effect was temporary and was reversed by long-term (2 days) incubation with WNK463. Accordingly, 2 days (but not 2 h) inhibition of p38-MAPK or its upstream activators ASK1 or TAK1, or WNKs, diminished regulatory volume increase (RVI) following cell shrinkage under hyperosmolarity. We also show that RVI mediated by the ion transporter NKCC1 is dependent on p38-MAPK. Since WNKs are known activators of NKCC1, we propose a WNK- > NKCC1- > p38-MAPK pathway that controls RVI. This pathway is augmented by NHE1. Additionally, hyperosmolarity inhibited mTORC1 activation and cell proliferation. Thus, activation of p38-MAPK and WNKs is important for RVI and for cell proliferation.
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