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Non‐apoptotic caspase‐8 activation balances T lymphocyte autophagy
Author(s) -
Bell Bryan Daniel,
Leverrier Sabrina,
Weist Brian,
Morrissette Naomi,
Walsh Craig
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.662.9
Subject(s) - fadd , autophagy , atg5 , microbiology and biotechnology , programmed cell death , necroptosis , caspase 8 , apoptosis , death domain , biology , chemistry , caspase , cancer research , biochemistry
FADD and caspase‐8 (casp8) transduce an apoptotic signal through tumor necrosis factor family members. Paradoxically, lymphocytes lacking FADD or casp8 function fail to undergo normal clonal expansion and instead succumb to caspase‐independent cell death. However, the exact nature of the survival defects of these T cells has remained elusive. We show that T cells lacking FADD or casp8 are subject to hyperactive autophagic signaling. FADD‐deficient embryonic fibroblasts and Jurkats also possessed elevated levels of autophagy compared to wild type cells. T cell autophagy induced casp8 activation through an interaction with FADD:Atg5‐Atg12 complexes. Inhibition of autophagic signaling with 3‐methyladenine, or by expression of dominant‐negative Vps34, rescued T cells expressing a dominant‐negative FADD protein. Since the necroptosis inhibitor Nec‐1 also rescued T cells lacking FADD or casp8 function, our findings demonstrate that while autophagy is necessary for rapid T cell proliferation, FADD and casp8 form a feedback loop to limit autophagy and prevent this salvage pathway from inducing type‐II cell death. These results suggest that, by linking autophagy mediators to cell death executioners, hyperautophagic conditions promote apoptotic cell death, thus avoiding an inflammatory response induced by type‐II cell death in vivo . Support from NIH (T32CA09054, BDB; R01AI50506, CMW).