Editors' ChoiceCell Biology

Autophagy Limits Innate Immune Signaling

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Science Signaling  30 Sep 2014:
Vol. 7, Issue 345, pp. ec267
DOI: 10.1126/scisignal.2005964

Autophagy is a process that enables cells to survive periods of starvation through the targeted degradation of cellular components to provide carbon and nitrogen for metabolism and molecular biosynthesis. Some cancer cells are “addicted” to this process and basal autophagy is increased in these cells. Mathew et al. performed proteomic analyses of Ras-transformed mouse cell lines that were either wild-type or deficient in the essential autophagy gene Atg5. Using bioinformatics analysis, they identified a specific subset of proteins involved in innate immune signaling that were increased in abundance in Atg5-deficient Ras-transformed cells. These included components of the RLR (RIG-I-like receptor) pathway (intracellular pathogen-sensing pathway), the TLR (Toll-like receptor) pathway (primarily a cell surface pathogen-sensing pathway), and the JAK-STAT pathway (pathway activated by proinflammatory cytokines). Stimulation of RLR or TLR signaling resulted in increased dimerization (activation) of the transcription factor interferon receptor factor 3 (IRF3) in Atg5-deficient cells compared with that in Atg5 wild-type cells. Analysis of transcriptional changes in response to starvation showed that Atg5-deficient cells had increased expression of genes involved in the interferon (IFN) response compared to the Ras-transformed cells with intact Atg5. Moreover, in basal (nutrient-replete) conditions, Atg5-deficient cells had increased amounts of STAT1, which mediates the IFN response. Stimulus-induced activation of interleukin-6 (IL-6) or IFN-β reporter genes and production of the proinflammatory cytokines IL-6, IFN-α, and IFN-β were greater in Atg5-deficient cells compared with Atg5 wild-type Ras-transformed cells. The viability of Atg5-deficient cells was compromised in response to various stimuli that activated the innate immune signaling pathways, and the addition of neutralizing antibodies to IFNs reduced cell death in response to these stimuli. Although caspase-3 cleavage, an indicator of apoptotic cell death, was increased in the Atg5-deficient cells exposed to stimuli of the innate immune signaling pathways, inhibition of caspases resulted in an increase in cell death through a necrotic cell death pathway. Thus, in addition to supplying building blocks for metabolism and biosynthesis, autophagy limits the accumulation of sensors and mediators of the innate immune system, limiting cellular toxicity to molecules that activate these pathways.

R. Mathew, S. Khor, S. R. Hackett, J. D. Rabinowitz, D. H. Perlman, E. White, Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol. Cell 55, 916–930 (2014). [PubMed]

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