Chmp4b,也称为charged multivesicular body protein 4B,是哺乳动物细胞中ESCRT-III复合体的核心亚基之一。ESCRT-III复合体负责多种生物膜的重塑和分裂过程,包括细胞分裂时细胞膜的分离、病毒样颗粒的释放、细胞凋亡和自噬等。Chmp4b在这些过程中发挥重要作用,参与调控细胞膜结构的维持和动态变化。
在多种疾病中,Chmp4b的表达和功能发生变化,影响疾病的发生和发展。例如,Chmp4b在阿尔茨海默病(AD)中发挥重要作用。研究发现,Chmp4b在AD患者和模型小鼠的海马组织中表达下调,且与AD的严重程度呈负相关[1]。进一步研究表明,Chmp4b在AD的炎症反应中发挥重要作用,通过抑制GSDMD减轻小胶质细胞焦亡,从而减轻炎症反应[1]。
Chmp4b还与白内障的发生发展密切相关。研究发现,Chmp4b基因的突变与多种类型的白内障相关,包括进行性儿童后囊下白内障和后极性白内障[2]。Chmp4b在晶状体上皮细胞和纤维细胞中表达,其功能缺失会导致晶状体细胞凋亡和分化异常,进而导致白内障的发生[4]。此外,Chmp4b还与HSP90β相互作用,共同抑制白内障的发生[3]。
在创伤性脑损伤(TBI)中,Chmp4b的表达和功能发生变化。研究发现,上调Chmp4b的表达可以减轻TBI后小胶质细胞坏死性凋亡,改善神经功能恢复并保护细胞免受死亡[6]。进一步研究表明,FOXO1转录因子通过结合CHMP4B启动子区域,上调CHMP4B的表达,从而抑制坏死性凋亡[6]。
在肝细胞癌(HCC)中,Chmp4b的表达与患者的预后密切相关。研究发现,Chmp4b在HCC组织中表达上调,且与HCC患者的多项临床病理参数相关,包括AFP、肝硬化、AJCC分期、Ki-67表达和不良预后等[5]。进一步研究表明,下调Chmp4B的表达可以导致HCC细胞周期阻滞和增殖受损,增加HCC细胞对多柔比星的敏感性[5]。此外,Chmp4b还与肝癌细胞的增殖和耐药性相关[5]。
此外,Chmp4b在细胞连接和细胞骨架的形成中也发挥重要作用。研究发现,Chmp4B与间隙连接蛋白Cx46和Cx50形成复合物,参与晶状体纤维细胞分化的过程中[7]。此外,Chmp4B还定位在初级纤毛中,参与纤毛的组装和维护[8]。
综上所述,Chmp4b是一种多功能蛋白质,参与多种细胞生物学过程,包括细胞膜的重塑、细胞凋亡、细胞增殖、细胞连接和细胞骨架的形成等。Chmp4b在多种疾病中发挥重要作用,包括阿尔茨海默病、白内障、创伤性脑损伤和肝细胞癌等。Chmp4b的研究有助于深入理解细胞生物学过程和疾病发生机制,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Ding, Yi, Li, Shi-Yao, Lv, Wei, Zhang, Zhi-Yuan, Lu, Xiao-Wei. 2024. Pyroptosis Signature Gene CHMP4B Regulates Microglia Pyroptosis by Inhibiting GSDMD in Alzheimer's Disease. In Molecular neurobiology, 62, 77-90. doi:10.1007/s12035-024-04255-9. https://pubmed.ncbi.nlm.nih.gov/38823000/
2. Shiels, Alan, Bennett, Thomas M, Knopf, Harry L S, Shim, Soomin, Hanson, Phyllis I. 2007. CHMP4B, a novel gene for autosomal dominant cataracts linked to chromosome 20q. In American journal of human genetics, 81, 596-606. doi:. https://pubmed.ncbi.nlm.nih.gov/17701905/
3. Fu, Jia-Ling, Zheng, Shu-Yu, Wang, Yan, Xie, Liu-Liu, Li, David Wan-Cheng. 2023. HSP90β prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2221522120. doi:10.1073/pnas.2221522120. https://pubmed.ncbi.nlm.nih.gov/37487085/
4. Zhou, Yuefang, Bennett, Thomas M, Shiels, Alan. 2019. A charged multivesicular body protein (CHMP4B) is required for lens growth and differentiation. In Differentiation; research in biological diversity, 109, 16-27. doi:10.1016/j.diff.2019.07.003. https://pubmed.ncbi.nlm.nih.gov/31404815/
5. Hu, Baoying, Jiang, Dawei, Chen, Yuyan, Lu, Cuihua, Wan, Chunhua. 2015. High CHMP4B expression is associated with accelerated cell proliferation and resistance to doxorubicin in hepatocellular carcinoma. In Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 36, 2569-81. doi:10.1007/s13277-014-2873-1. https://pubmed.ncbi.nlm.nih.gov/25874485/
6. Zhao, Pengzhan, Li, Chong, Chen, Binglin, Du, Xiaoliu, Ji, Jing. 2020. Up-regulation of CHMP4B alleviates microglial necroptosis induced by traumatic brain injury. In Journal of cellular and molecular medicine, 24, 8466-8479. doi:10.1111/jcmm.15406. https://pubmed.ncbi.nlm.nih.gov/32585748/
7. Zhou, Yuefang, Bennett, Thomas M, White, Thomas W, Shiels, Alan. . Charged multivesicular body protein 4b forms complexes with gap junction proteins during lens fiber cell differentiation. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e22801. doi:10.1096/fj.202201368RR. https://pubmed.ncbi.nlm.nih.gov/36880430/
8. Jung, Eunji, Choi, Tae-Ik, Lee, Ji-Eun, Kim, Cheol-Hee, Kim, Joon. 2019. ESCRT subunit CHMP4B localizes to primary cilia and is required for the structural integrity of the ciliary membrane. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34, 1331-1344. doi:10.1096/fj.201901778R. https://pubmed.ncbi.nlm.nih.gov/31914703/