RT Journal Article
SR Electronic
T1 Pleiotropy of Bcl-2 family proteins is an ancient trait in the metazoan evolution
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 816322
DO 10.1101/816322
A1 Nikolay Popgeorgiev
A1 Lea Jabbour
A1 Trang Thi Minh Nguyen
A1 Nikola Ralchev
A1 Rudy Gadet
A1 Stéphen Manon
A1 Hans-Jürgen Osigus
A1 Bernd Schierwater
A1 Ruth Rimokh
A1 Germain Gillet
YR 2019
UL http://biorxiv.org/content/early/2019/10/24/816322.abstract
AB In the animal kingdom, proteins of the Bcl-2 family are widely recognized as regulators of mitochondrial outer membrane permeabilization (MOMP), leading to apoptotic cell death. These proteins were recently also shown to control IP3-dependent calcium fluxes at the level of the endoplasmic reticulum (ER). However, the origin and evolution of these pleiotropic functions remain elusive. Here, we molecularly characterized the four members of the Bcl-2 family (trBcl-2L1 to -2L4) in the most primitive metazoan, namely Trichoplax adhaerens. Primary structure and phylogenetic analyses demonstrated that all four trBcl-2 homologs belong to the multidomain Bcl-2 group and presented a conserved C-terminus transmembrane (TM) domain. TrBcl-2L1 and trBcl-2L2 are highly divergent proteins clustering with the anti-apoptotic Bcl-2 members, whereas trBcl-2L3 and trBcl-2L4 were homologous to the pro-apoptotic Bax (trBax) and Bak (trBak). Interestingly, at the functional level, trBak operates as a BH3 only sensitizer repressing the anti-apoptotic activities of trBcl-2L1 and trBcl-2L2, whereas trBax leads to MOMP, similarly to the well-known indirect model of Bax activation. Finally, we found that trBcl-2L1 had a dual ER and mitochondrial subcellular localization and was able to bind to IP3R. By generating two TM domain mutants we demonstrated that trBcl-2L1 targeted to the ER was able to control IP3-dependent calcium fluxes, whereas Mito-trBcl-2L1 represses trBax-dependent MOMP, suggesting that Bcl-2 pleiotropy appeared early and was conserved throughout metazoan evolution.