Knockdown of endoplasmic reticulum chaperone BiP leads to the death of parvocellular AVP / CRH neurons in mice
Knockdown of endoplasmic reticulum chaperone BiP leads to the death of parvocellular AVP / CRH neurons in mice
复制标题
内质网伴侣 BiP 的敲低导致小鼠细小细胞 AVP / CRH 神经元死亡
DOI：
10.1111/jne.13223
复制
发表时间：
2022
影响因子：
3.2
通讯作者：
Arima Hiroshi
中科院分区：
文献类型：
--
作者：
Kawaguchi Yohei;Hagiwara Daisuke;Tsumura Tetsuro;Miyata Takashi;Kobayashi Tomoko;Sugiyama Mariko;Onoue Takeshi;Yasuda Yoshinori;Iwama Shintaro;Suga Hidetaka;Banno Ryoichi;Grinevich Valery;Arima Hiroshi
精氨酸抗利尿激素（AVP）在室旁核的大细胞（magnAVP）和旁细胞AVP （parvAVP）神经元中均有表达，且AVP仅在旁细胞神经元中与促肾上腺皮质激素释放激素（CRH）共定位。免疫球蛋白重链结合蛋白（BiP）是一种主要的内质网伴侣蛋白，在内质网胁迫下调节未折叠蛋白的反应。我们之前已经证明，magnAVP神经元中BiP的下调会加剧内质网应激，从而导致自噬相关的magnAVP神经元细胞死亡。使用相同的方法，在本研究中，我们研究了BiP在小鼠parvAVP/CRH神经元中的作用。我们的数据表明，在非应激条件下，BiP在小鼠parvAVP/CRH神经元中表达，并且与肾上腺切除术后CRH表达的增加成比例上调。对于parvAVP/CRH神经元中的BiP敲低，我们使用病毒方法结合shRNA干扰。敲低BiP表达诱导parvAVP/CRH神经元内质网应激，通过C/EBP同源蛋白的表达反映。此外，BiP敲低导致4周后parvAVP/CRH神经元的丢失。综上所述，我们的研究结果表明，BiP在parvAVP/CRH神经元中起关键作用，parvAVP/CRH神经元作为神经内分泌细胞产生大量分泌蛋白。
Arginine vasopressin (AVP) is expressed in both magnocellular (magnAVP) and parvocellular AVP (parvAVP) neurons of the paraventricular nucleus, and AVP colocalizes with corticotropin‐releasing hormone (CRH) only in the parvocellular neurons. The immunoglobulin heavy chain binding protein (BiP) is a major endoplasmic reticulum (ER) chaperone which regulates the unfolded protein response under ER stress. We previously demonstrated that knockdown of BiP in magnAVP neurons exacerbated ER stress, which resulted in the autophagy‐associated cell death of magnAVP neurons. Using the same approach, in the present study we examined the role of BiP in mouse parvAVP/CRH neurons. Our data demonstrate that BiP is expressed in mouse parvAVP/CRH neurons under nonstress conditions and is upregulated in proportion to the increase in CRH expression after adrenalectomy. For BiP knockdown in parvAVP/CRH neurons, we utilized a viral approach in combination with shRNA interference. Knockdown of BiP expression induced ER stress in parvAVP/CRH neurons, as reflected by the expression of C/EBP homologous protein. Furthermore, BiP knockdown led to the loss of parvAVP/CRH neurons after 4 weeks. In summary, our results demonstrate that BiP plays a pivotal role in parvAVP/CRH neurons, which function as neuroendocrine cells producing a large number of secretory proteins.