BCL2L13 explained

BCL2-like 13 (apoptosis facilitator), also known as BCL2L13 or Bcl-rambo, is a protein which in humans is encoded by the BCL2L13 gene on chromosome 22. This gene encodes a mitochondrially-localized protein which is classified under the Bcl-2 protein family. Overexpression of the encoded protein results in apoptosis.^{[1] [2]} As a result, it has been implicated in cancers such as childhood acute lymphoblastic leukemia (ALL) and glioblastoma multiforme (GBM).^{[3] [4]} Alternatively spliced transcript variants have been observed for this gene, such as Bcl-rambo beta.^{[1] [5]}

Structure

As a member of the Bcl-2 protein family, Bcl-rambo comprises four conserved BH domains and a transmembrane (TM) domain. However, unlike the other members, Bcl-rambo does not require the BH domains for its apoptotic function, relying instead on the mitochondrial localization carried out by the TM domain. In addition to these domains, it has conserved B-cell lymphoma 2 homology motifs, as well as an extension at its c-terminal, termed the BHNo domain, which contains two tandem repeats, RTA and RTB.^{[1] [5]}

An alternatively-spliced protein variant, called Bcl-rambo beta, is composed of only the BH4 domain, completely lacking the BH domains 1 through 3 due to an in-frame stop codon inserted by an Alu element. Without the TM domain, this variant remains in the cytosol and does not localize to the mitochondria. Nonetheless, it still performs proapoptotic activity, mediated by the encoded Alu element, though the exact mechanisms remain to be elucidated.^[6]

Function

Bcl-rambo is a member of the Bcl-2 family of proteins that regulate apoptosis. In cells, Bcl-rambo is localized to the mitochondria, and its overexpression induces apoptosis that is blocked by caspase inhibitors, whereas inhibitors controlling upstream events of either the 'death receptor' (FLIP, FADD-DN) or the 'mitochondrial' pro-apoptotic pathway (Bcl-x(L)) had no effect.^[2] Bcl-rambo mediates apoptosis by associating with adenine nucleotide translocator (ANT), a component of the mitochondrial permeability transition pore, to induce its opening. ANT will also facilitate the transfer of ADP and ATP between the cytosol and the matrix.^[5]

Clinical significance

The BCL2L13 gene has been implicated in a wide spectrum of cancers. Previous clinical studies observed in ALL patients that high expression of BCL2L13 correlated to lower event-free and overall survival. Though statistically significant, the observations contradict the accepted pro-apoptotic function of BCL2L13’s gene product, which should have contributed to cancer cell death and, thus, more favorable survival outcomes. Two possible explanations propose that either 1) Bcl-rambo performs a different biological role in childhood, or 2) alternative splicing could have generated an anti-apoptotic variant. More research is necessary to resolve this discrepancy.^[3] In another type of cancer, GBM, Bcl-rambo is known to inhibit induced apoptosis in GBM cells by binding two other pro-apoptotic proteins, ceramide synthases 2 (CerS2) and 6 (CerS6), thereby blocking CerS2/6 complex formation and activity. Thus, inhibiting BCL2L13 during cancer treatments may improve survival outcomes.^[4]

Interactions

BCL2L13 has been shown to interact with:

• CerS2^[4] and
• CerS6.^[4]

Further reading

• Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP . The DNA sequence of human chromosome 22 . Nature . 402 . 6761 . 489–95 . Dec 1999 . 10591208 . 10.1038/990031 . 1999Natur.402..489D . free .
• Kataoka T, Holler N, Micheau O, Martinon F, Tinel A, Hofmann K, Tschopp J . Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension . The Journal of Biological Chemistry . 276 . 22 . 19548–54 . Jun 2001 . 11262395 . 10.1074/jbc.M010520200 . free .
• Footz TK, Brinkman-Mills P, Banting GS, Maier SA, Riazi MA, Bridgland L, Hu S, Birren B, Minoshima S, Shimizu N, Pan H, Nguyen T, Fang F, Fu Y, Ray L, Wu H, Shaull S, Phan S, Yao Z, Chen F, Huan A, Hu P, Wang Q, Loh P, Qi S, Roe BA, McDermid HE . Analysis of the cat eye syndrome critical region in humans and the region of conserved synteny in mice: a search for candidate genes at or near the human chromosome 22 pericentromere . Genome Research . 11 . 6 . 1053–70 . Jun 2001 . 11381032 . 311098 . 10.1101/gr.154901 .
• Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I . A genome annotation-driven approach to cloning the human ORFeome . Genome Biology . 5 . 10 . R84 . 2005 . 15461802 . 545604 . 10.1186/gb-2004-5-10-r84 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . Nov 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .
• Banga S, Gao P, Shen X, Fiscus V, Zong WX, Chen L, Luo ZQ . Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family . Proceedings of the National Academy of Sciences of the United States of America . 104 . 12 . 5121–6 . Mar 2007 . 17360363 . 1829273 . 10.1073/pnas.0611030104 . 2007PNAS..104.5121B . free .

Notes and References

1. Web site: Entrez Gene: BCL2L13 BCL2-like 13 (apoptosis facilitator).
2. Kataoka T, Holler N, Micheau O, Martinon F, Tinel A, Hofmann K, Tschopp J . Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension . The Journal of Biological Chemistry . 276 . 22 . 19548–54 . Jun 2001 . 11262395 . 10.1074/jbc.M010520200 . free .
3. Yang YL, Lin SR, Chen JS, Lin SW, Yu SL, Chen HY, Yen CT, Lin CY, Lin JF, Lin KH, Jou ST, Hu CY, Chang SK, Lu MY, Chang HH, Chang WH, Lin KS, Lin DT . Leukemia Research 34-18-23.pdf Expression and prognostic significance of the apoptotic genes BCL2L13, Livin, and CASP8AP2 in childhood acute lymphoblastic leukemia . Leukemia Research . 34 . 1 . 18–23 . Jan 2010 . 20109966 . 10.1016/j.leukres.2009.07.023 .
4. Jensen SA, Calvert AE, Volpert G, Kouri FM, Hurley LA, Luciano JP, Wu Y, Chalastanis A, Futerman AH, Stegh AH . Bcl2L13 is a ceramide synthase inhibitor in glioblastoma . Proceedings of the National Academy of Sciences of the United States of America . 111 . 15 . 5682–7 . Apr 2014 . 24706805 . 10.1073/pnas.1316700111 . 2014PNAS..111.5682J . 3992626. free .
5. Kim JY, So KJ, Lee S, Park JH . Bcl-rambo induces apoptosis via interaction with the adenine nucleotide translocator . FEBS Letters . 586 . 19 . 3142–9 . Sep 2012 . 22921587 . 10.1016/j.febslet.2012.08.015 . 31709574 . free .
6. • Yi P, Zhang W, Zhai Z, Miao L, Wang Y, Wu M . Bcl-rambo beta, a special splicing variant with an insertion of an Alu-like cassette, promotes etoposide- and Taxol-induced cell death . FEBS Letters . 534 . 1–3 . 61–8 . Jan 2003 . 12527362 . 10.1016/S0014-5793(02)03778-X . 7018829 . free .