Wang Jie, Lee Jessica, Liem David, Ping Peipei
Departments of Physiology, Medicine (Cardiology) and Bioinformatics, NIH BD2K Center of Excellence for Biomedical Computing, University of California Los Angeles, Los Angeles, CA 90095, USA.
Departments of Physiology, Medicine (Cardiology) and Bioinformatics, NIH BD2K Center of Excellence for Biomedical Computing, University of California Los Angeles, Los Angeles, CA 90095, USA.
Gene. 2017 Jun 30;618:14-23. doi: 10.1016/j.gene.2017.03.005. Epub 2017 Mar 7.
The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen. As a highly conserved molecular chaperone, BiP assists in a wide range of folding processes via its two structural domains, a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). BiP is also an essential component of the translocation machinery for protein import into the ER, a regulator for Ca homeostasis in the ER, as well as a facilitator of ER-associated protein degradation (ERAD) via retrograde transportation of aberrant proteins across the ER membrane. When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. Post-translational modifications (PTMs) of BiP have been shown to regulate BiP's activity, turnover, and availability upon different extrinsic or intrinsic stimuli. As a master regulator of ER function, BiP is associated with cancer, cardiovascular disease, neurodegenerative disease, and immunological diseases. BiP has been targeted in cancer therapies and shows promise for application in other relevant diseases.
HSPA5基因编码结合免疫球蛋白蛋白（BiP），一种定位于内质网腔的Hsp70家族伴侣蛋白。作为一种高度保守的分子伴侣，BiP通过其两个结构域，即核苷酸结合结构域（NBD）和底物结合结构域（SBD），协助多种折叠过程。BiP也是蛋白质导入内质网的转运机制的重要组成部分，是内质网中钙稳态的调节因子，也是通过异常蛋白跨内质网膜的逆行转运促进内质网相关蛋白降解（ERAD）的因子。当内质网中未折叠/错误折叠的蛋白超过蛋白质折叠机制的能力时，BiP可以启动未折叠蛋白反应（UPR），减少未折叠/错误折叠蛋白的负荷，诱导自噬，并与凋亡机制相互作用以协助细胞做出生存决定。BiP的翻译后修饰（PTM）已被证明可在不同的外在或内在刺激下调节BiP的活性、周转和可用性。作为内质网功能的主要调节因子，BiP与癌症、心血管疾病、神经退行性疾病和免疫性疾病有关。BiP已成为癌症治疗的靶点，并有望应用于其他相关疾病。
