BAP31在小鼠中的功能解析

BAP31 is an evolutionarily-conserved, ubiquitously-expressed, polytopic integral membrane protein of the endoplasmic reticulum (ER). Originally BAP31 was identified as a binding partner of a B cell receptor. Bap31 has been implicated in the ER sorting of diverse client membrane proteins, thereby promoting the vesicular transport from the ER to Golgi. Our lab identified BAP31 as a Bcl-2/Bcl-XL interacting protein in 1997, and then we found that P20, a dominant negative cleaved form of Bap31, causes rapid transmission of ER calcium signals to mitochondria where it stimulates DRP1-dependent organelle fission and cytochrome c release. We further found that BAP31 associates with gamma-actin, which implied that BAP31 may play a fundamental role in the structure organization of the cytoplasm. We constructed unique split-ubiquitin-linked cDNA libraries and implemented this system to screen for binding partners of membrane protein bait for the first time in the world. We found that BAP31 interacts with the Sec61 translocon, and promotes unfold proteins retrotranslocation from the ER for the degradation by the cytoplasmic 26S proteasome system. Knockdown of BAP31 by genomic targeting causes prenatal lethality in mice. It is very important to study BAP31 functions through mouse phenotype. A convenient way around this problem is the use of Cre-Lox recombination to generate a conditional knockout animal, in which a gene is only knocked out in a specific tissue or at a specific time. We will create tissue specific knockdown mice in both immune cells and neuron cells, respectively. Several lines of documents have shown that Bap31 may regulate the nervous system. e.g. BAP31 is up-regulated in the hippocampus of fatigued mice. We identified that BAP31 interacts with reticulon 3 (RTN 3) and RTN-4B) (unpublished results). RTN 3 is primarily in pyramidal neurons of the human cerebral cortex and interacts with beta-secretase to inhibit its activity to produce beta-amyloid protein. In addition, Bap31 may regulate immune cells secreting cytokines and plasma membrane protein rearrangment. Since BAP31 associates with the B cell receptor and retains immature IgD at the ER; both BAP31 and reticulon are a class of sorting proteins that control the process for secretory proteins, and T cell receptor complex are assembled and transported in the ER; RTN-4B is involved in the inflammation through Th2 and neutrophil cells. Taken together, current information suggests that BAP31 and the reticulon family may both play important roles in nervous and immune system. The current study will focus on: 1) How BAP31 regulating Alzheimer diseases; 2)Investigating the effects of BAP31 on the inflammation and the function of T cells. We believe that this study will open a door into a new field within the correspponding diseses.

BAP31是广泛表达的内质网膜蛋白，目前已经发现它能与一些重要的生物大分子结合，从而参与多种蛋白的调节和代谢。我们团队首先阐明了BAP31在细胞凋亡、蛋白质降解等调节通路中的作用机制。最近发现BAP31与浆膜蛋白结合于内质网。因为浆膜蛋白与阿尔茨海默病的发生直接相关；浆膜蛋白还通过T细胞和粒细胞 来调节炎症反应；此外，BAP31和浆膜蛋白都与MHCI相关又是分泌通路上的转运蛋白，T细胞受体复合物在此组装转运。因此，BAP31可能与神经及免疫系统相关联。但这些可能性还没有在体内得到证实，其主要原因是BAP31缺陷鼠及缺陷线虫都不能存活，至今还没有动物模型。据此，目前亟待构建BAP31的条件缺陷鼠。从而解决下面两方面问题：1）BAP31是否调节T细胞的功能，是否控制T细胞分泌细胞因子及调控细胞膜受体表达量；2）BAP31是否与阿尔茨海默病有关联。本研究将对相关神经及免疫疾病的治疗提供新依据。

BAP31 是广泛表达的内质网膜蛋白，目前已经发现它能与一些重要的生物大分子结合，从而参与多种蛋白的调节和代谢。我们团队首先阐明了 BAP31 在细胞凋亡、蛋白质降解等调节通路中的作用机制。另外，最近发现 BAP31 与浆膜蛋白结合于内质网。因为浆膜蛋白与阿尔茨海默病的发生直接相关；浆膜蛋白还通过 T 细胞和粒细胞 来调节炎症反应；此外，BAP31 和浆膜蛋白都与 MHCI 相关又是分泌通路上的转运蛋白，T 细胞受体复合物在此组装转运。因此，BAP31 可能与神经及免疫系统相关联。但这些可能性还没有在体内得到证实，其主要原因是 BAP31 缺陷鼠及缺陷线虫都不能存活，至今还没有动物模型。据此，目前亟待构建 BAP31 的条件缺陷鼠。从而解决下面两方面问题：1）BAP31是否调节 T 细胞的功能，是否控制 T 细胞分泌细胞因子及调控细胞膜受体表达量；2）BAP31 是否与阿尔茨海默病有关联。本研究将对相关神经及免疫疾病的治疗提供新依据。.在世界上首次成功构建BAP31动物模型-条件缺陷鼠，首次发现BAP31与T细胞功能和老年痴呆病的关系。同时拓展了BAP31与脂肪肝、肥胖、炎症驱化、小胶质细胞的活化等相关性研究，为课题更进一步研究打下坚实的基础。