PROGRESSES OF BCL-2 PROTEINS IN TELEOST FISH AND MAMMALS

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 Ca²⁺ 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 Ca²⁺ release in the ER. Fish Nrz can interact with IP₃R1 to regulate Ca²⁺ release in ER. In addition, fish Bid and Bax can regulate Ca²⁺ 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.