title: Caspase-8 isoform 6 promotes death effector filament formation independent of microtubules.
abstract: Caspase-8 can trigger cell death following prodomain-mediated recruitment to the 'death-inducing signaling complex.' The prodomain consists of two death effector domain (DED) motifs that undergo homotypic interactions within the cell. Aside from mediating recruitment of procaspase-8, the prodomains have also been implicated in regulating cell survival, proliferation, death, senescence, differentiation, and substrate attachment. Here, we perform the initial characterization of a novel isoform of caspase-8, designated caspase-8 isoform 6 (Casp-8.6), which encodes both prodomain DEDs followed by a unique C-terminal tail. Casp-8.6 is detected in cells of the hematopoietic compartment as well as several other tissues. When Casp-8.6 expression is reconstituted in caspase-8-deficient cells, Casp-8.6 does not significantly impact cellular proliferation, contrasting with our previous results using a domain-defined 'DED-only' construct that lacks the C-terminal tail. Like the DED-only construct, Casp-8.6 also robustly forms 'death effector' filaments, but in contrast to the DED construct, it does not exhibit a dependence upon intact microtubules to scaffold filament formation. Both types of death effector filaments promote apoptosis when expressed in the presence of full length caspase-8 (isoform 1). Together, the results implicate Casp-8.6 as a new physiological modulator of apoptosis.
authors.affiliation: Moores UCSD Cancer Center, 3855, Health Sciences Drive, La Jolla, CA 92039-0803, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Yuan
authors.forename: Shanique
authors.initials: S
authors.lastname: Young
authors.forename: Jesse
authors.initials: J
authors.lastname: Liang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schmid
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mielgo
authors.forename: Dwayne G
authors.initials: DG
authors.lastname: Stupack
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8 / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism
chemical_list: C116096:DEDD protein, human; D004268:DNA-Binding Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D053181:Caspase 8