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Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif
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  • Journal title : BMB Reports
  • Volume 49, Issue 5,  2016, pp.282-287
  • Publisher : Korean Society for Biochemistry and Molecular Biology
  • DOI : 10.5483/BMBRep.2016.49.5.245
 Title & Authors
Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif
Han, Ji Hye; Moon, Ae Ran; Chang, Jeong Hwan; Bae, Jeehyeon; Choi, Jin Myung; Lee, Sung Haeng; Kim, Tae-Hyoung;
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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a homo-trimeric cytotoxic ligand. Several studies have demonstrated that incorporation of artificial trimerization motifs into the TRAIL protein leads to the enhancement of biological activity. Here, we show that linkage of the isoleucine zipper hexamerization motif to the N-terminus of TRAIL, referred as ILz(6):TRAIL, leads to multimerization of its trimeric form, which has higher cytotoxic activity compared to its native state. Size exclusion chromatography of ILz(6):TRAIL revealed possible existence of various forms such as trimeric, hexameric, and multimeric (possibly containing one-, two-, and multi-units of trimeric TRAIL, respectively). Increased number of multimerized ILz(6):TRAIL units corresponded with enhanced cytotoxic activity. Further, a high degree of ILz(6):TRAIL multimerization triggered rapid signaling events such as activation of caspases, tBid generation, and chromatin condensation. Taken together, these results indicate that multimerization of TRAIL significantly enhances its cytotoxic activity.
Apoptosis;Cell death;Isoleucine zipper;Multimerization;TRAIL;
 Cited by
Wiley SR, Schooley K, Smolak PJ et al (1995) Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673-682 crossref(new window)

Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A and Ashkenazi A (1996) Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 271, 12687-12690 crossref(new window)

Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J and Hood L (1997) Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 7, 821-830 crossref(new window)

Schneider P, Thome M, Burns K et al (1997) TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7, 831-836 crossref(new window)

Sheridan JP, Marsters SA, Pitti RM et al (1997) Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818-821 crossref(new window)

Hymowitz SG, Christinger HW, Fuh G et al (1999) Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell 4, 563-571 crossref(new window)

Iaccarino G, Smithwick LA, Lefkowitz RJ and Koch WJ (1999) Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis. Proc Natl Acad Sci U S A 96, 3945-3950 crossref(new window)

Mongkolsapaya J, Grimes JM, Chen N et al (1999) Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation. Nat Struct Biol 6, 1048-1053 crossref(new window)

Jeong M, Kwon YS, Park SH et al (2009) Possible novel therapy for malignant gliomas with secretable trimeric TRAIL. PloS ONE 4, e4545 crossref(new window)

Walczak H, Miller RE, Ariail K et al (1999) Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5, 157-163 crossref(new window)

Berg D, Stuhmer T, Siegmund D et al (2009) Oligomerized tumor necrosis factor-related apoptosis inducing ligand strongly induces cell death in myeloma cells, but also activates proinflammatory signaling pathways. FEBS Lett 276, 6912-6927 crossref(new window)

O'Shea EK, Rutkowski R, Stafford WF 3rd and Kim PS (1989) Preferential heterodimer formation by isolated leucine zippers from fos and jun. Science 245, 646-648 crossref(new window)

Harbury PB, Zhang T, Kim PS and Alber T (1993) A switch between two-, three-, and four-stranded coiled coils in GCN4 leucine zipper mutants. Science 262, 1401-1407 crossref(new window)

Morris AE, Remmele RL Jr, Klinke R, Macduff BM, Fanslow WC and Armitage RJ (1999) Incorporation of an isoleucine zipper motif enhances the biological activity of soluble CD40L (CD154). J Biol Chem 274, 418-423 crossref(new window)

Cui D, Wang S, Chen Y et al (2010) An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand. Cell Mol Immunol 7, 316-322 crossref(new window)

Shiraishi T, Suzuyama K, Okamoto H et al (2004) Increased cytotoxicity of soluble Fas ligand by fusing isoleucine zipper motif. Biochem Biophys Res Commun 322, 197-202 crossref(new window)