鱼类和哺乳类Bcl-2家族蛋白的研究进展

PROGRESSES OF BCL-2 PROTEINS IN TELEOST FISH AND MAMMALS

细胞凋亡,即细胞程序性死亡,在多细胞生物的发育和稳态调控过程中发挥关键作用。Bcl-2家族蛋白是凋亡过程中的主要调控因子,关于Bcl-2家族蛋白在凋亡过程中的功能及其作用机制一直是研究的热点。已有研究显示Bcl-2家族蛋白不仅作用于线粒体引发凋亡,并且参与了包括对细胞内质网Ca^(2+)的调控、DNA损伤的修复及与自噬的相互作用等多种反应,从多方面对细胞的生存状态进行调控。Bcl-2家族蛋白保守存在于脊椎动物和无脊椎动物中,其功能在进化中存在异同。文章以高等脊椎动物(哺乳动物)和低等脊椎动物(硬骨鱼类)为代表,总结了近年来Bcl-2家族蛋白在调控宿主凋亡与自噬、DNA损伤及新陈代谢等方面取得的最新进展。该研究为深入了解鱼类和哺乳类Bcl-2家族蛋白的功能和作用机制提供了重要参考。

Apoptosis(programmed cell death)plays key roles in the development and homeostasis of multicellular organisms.B-cell lymphoma 2(Bcl-2)family proteins are the major regulators in the process of apoptosis.According to the presence of conserved Bcl-2 homology(BH)domains and functions in apoptosis,the Bcl-2 family can be classified into three subfamilies.The anti-apoptotic subfamily suppresses apoptotic which contains four BH domains(BH1-4)and mainly includes Bcl-2,Bcl-xL,myeloid cell leukemia 1(Mcl-1),A1,Bcl-B and Bcl-w.The pro-apoptotic subfamily also contains four BH domains and includes Bax,Bak and Bok.BH-3 only subfamily acts as pro-apoptotic proteins,but contains only BH3 domain which includes Bid,Bad,Bmf,Bik,Puma,Noxa,Hrk and Bnip3.Previous studies revealed that the Bcl-2 family proteins were multifunctional proteins,which not only act on mitochondria to induce apoptosis,but also participate in a variety of reactions including regulation of Ca^(2+)in the endoplasmic reticulum(ER),repair of DNA damage,interaction with autophagy proteins,and regulation of cell survival.In the present review,the functions of Bcl-2 proteins in mammals and fish were analyzed and compared,hoping to find the functional similarities and differences between mammalian and fish Bcl-2 proteins.For the regulation of cell apoptosis,mammalian Bcl-2 proteins(Bcl-2,Bcl-xL,Bax,Bak)mainly regulate the process of mitochondrial outer membrane permeabilization(MOMP).Fish Bcl-2 proteins,such as Mcl-1,Bad and Bcl-xL,can also involve in the MOMP process during virus infection to regulate cell apoptosis.Mammalian Bcl-2 proteins regulate the inositol 1,4,5-trisphosphate receptor(IP3R)mediated Ca^(2+)release in the ER.Fish Nrz can interact with IP3R1 to regulate Ca^(2+)release in ER.In addition,fish Bid and Bax can regulate Ca^(2+)release in ER through the ryanodine receptor(RyR)signaling pathway.Mammalian Bid,Bcl-xL and Puma involve in the reparations of DNA damage.Studies on the functions of Bcl-2 proteins in fish in DNA damage were limited.During DNA damage,fish Noxa was downregulated and Bcl-2 was upregulated,leading to the inhibition of apoptosis and keeping the embryos survive from the paternal DNA damage.In the process of autophagy,mammalian Bcl-2 proteins(Bcl-2,Bcl-xL,Bcl-w and Mcl-1)can inhibit autophagy by binding with autophagy gene Beclin-1.Fish p53 inhibit Bnip3 to protect the cell death caused by hypoxia.Mammalian Bad,Noxa and Bnips involve in the glycometabolism and lipid metabolism.Whilst,research on fish Bcl-2 in metabolism is scarce.Palmitic acid(PA)adding diet can increase the expression of Bim,Bid and Bax in zebrafish,indicating that fish Bcl-2 proteins also play roles in metabolism,but the mechanisms need further study.This review provides important reference for understanding the functions and mechanisms of Bcl-2 family proteins in fish and mammals.