Editors' ChoiceCell Biology

Life or Death Decisions

See allHide authors and affiliations

Science Signaling  28 Jan 2014:
Vol. 7, Issue 310, pp. ec30
DOI: 10.1126/scisignal.2005119

Autophagy, a process in which aggregated proteins and damaged organelles are degraded by lysosomes, can inhibit or promote apoptosis (see Joshi and Ryan). Gump et al. investigated the molecular mechanisms by which autophagy regulates apoptosis by the death receptor agonists Fas ligand and TRAIL. FACS analysis of proliferating BJAB B-cell lymphoma expressing a fluorescent reporter of autophagic flux identified high- and low-flux subpopulations. These differences in autophagic flux were transient and were not maintained after 24 hours of culture, suggesting that these differences were not due to genetic heterogeneity. Apoptosis in response to Fas ligand was greater in BJAB cells with high autophagic flux, whereas BJAB cells with low autophagic flux were more sensitive to apoptosis induced by TRAIL. Like the differences in autophagic flux, these differences in sensitivity to death receptor agonists were transient. Fas-induced apoptosis was decreased in BJAB cells treated with the autophagy inhibitor chloroquine but was not affected in chloroquine-treated Jurkat A3 cells. In addition, shRNAs directed against the autophagy factors Atg5 or Atg7 reduced Fas-induced, but not TRAIL-induced, apoptosis in BJAB cells or apoptosis triggered by either death receptor agonist in Jurkat cells. Dephosphorylation of Fas by the tyrosine phosphatase Fap-1 decreases the cell surface abundance and activity of Fas. Cells can be classified on the basis of the pathway through which Fas mediates cell death signaling as either type I, independent of mitochondrial signals, or type II, requiring mitochondrial signals. Fap-1 abundance was greater in BJAB cells (type I cells) with low autophagic flux than in those with high autophagic flux, and Fap-1 was not detectable in Jurkat cells (type II cells). Blocking autophagy with chloroquine treatment or shRNA knockdown of various autophagy factors, including Atg5 and Atg7 in BJAB and SKW6.4 cells (both of which are type I cells), resulted in increased Fap-1 abundance, suggesting that Fap-1 could be targeted by autophagic degradation, and reduced apoptosis in response to Fas ligand. In contrast, shRNA knockdown of autophagy components decreased cell viability in Jurkat cells. Jurkat cells that overexpressed wild-type Fap-1, but not a catalytically inactive Fap-1, behaved more like type I cells in that they were less sensitive to Fas ligand–induced apoptosis after chloroquine treatment. Conversely, BJAB cells that were deficient in Fap-1 behaved more like type II cells in that they showed increased sensitivity to Fas ligand–induced apoptosis after chloroquine treatment (although there were no differences in TRAIL-induced apoptosis). The autophagic adaptor protein p62 interacted with Fap-1 after Fas ligand stimulation and mediated its autophagic degradation, and knockdown of p62 in BJAB cells decreased sensitivity to Fas ligand–induced apoptosis. These results suggest that the abundance of Fap-1 determines whether autophagy protects cells against apoptosis triggered by Fas ligand.

J. M. Gump, L. Staskiewicz, M. J. Morgan, A. Bamberg, D. W. H. Riches, A. Thorburn, Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. Nat. Cell Biol. 16, 47–54 (2014). [PubMed]

S. Joshi, K. M. Ryan, Autophagy chews Fap to promote apoptosis. Nat. Cell Biol. 16, 23–25 (2014). [PubMed]

Stay Connected to Science Signaling