Caspase-8 isoform 6 promotes death effector filament formation independent of microtubules

• DOI: 10.1007/s10495-011-0677-y
• Publication Date: 2011-12-09T04:32:05Z
• Authors: Robert T. Yuan; Shanique Young; Jesse Liang; Michael C. Schmid; Ainhoa Mielgo; Dwayne G. Stupack
• Keywords: 0301 basic medicine; Caspase 8; Death Domain Receptor Signaling Adaptor Proteins; Molecular Sequence Data; Intracellular Signaling Peptides and Proteins; Apoptosis; Microtubules; DNA-Binding Proteins; 03 medical and health sciences; Humans; Protein Isoforms; Amino Acid Sequence; Cells, Cultured; Cell Proliferation

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.