ZBP1 Mediates Replicative Crisis through Telomere-to-Mitochondria Signaling

Transformed cells that have reached their replicative limit must overcome two barriers to gain immortality: replicative senescence and crisis. Crisis provides a redundant tumor-suppressive mechanism to replicative senescence that ultimately leads to the death of cells with unstable telomeres through a noncanonical form of autophagy. However, the molecular events that regulate crisis, especially those that act through dysfunctional telomeres, remain unclear. Nassour and colleagues sought to determine regulators of the crisis program and identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as one such regulator. Levels of the short isoform of ZBP1 [ZBP1(S)] are significantly induced in crisis through the cGAS–STING pathway. During crisis, ZBP1 induces IFN-stimulated genes (ISG), innate immune activation, and cell death, with depletion of IFN signaling or autophagy machinery components phenocopying the protective effects of ZBP1 loss, suggesting that ZBP1-driven cell death is dependent on both type I IFN and autophagy. Additionally, as replicative crisis is dependent on telomeres, loss of TRF2, a telomere protection factor, was also found to upregulate ZBP1(S) and type I IFN responses through TBK1 phosphorylation, indicating that the ZBP1-dependent IFN response during crisis is dependent on both cGAS–STING-mediated ZBP1(S) upregulation as well as a signal provided by dysfunctional telomeres. Investigation into the signal released by dysfunctional telomeres indicated that TERRA, long noncoding telomeric-repeat-containing RNA that are synthesized by dysfunctional telomeres, are sensed by ZBP1 through its Zα2 domain. TERRA-bound ZBP1 was found to form filamentous structures at the mitochondrial outer membrane (MOM), which, in turn, activates the innate immune adapter protein, mitochondrial antiviral signaling protein, that is anchored to the MOM and leads to the ZBP1-mediated IFN response and cell death. In summary, this study reveals a mechanism of telomere-mediated tumor suppression through activation of innate immunity and suggests this process is an evolutionary mechanism that inhibits the initiation of age-associated cancers through elimination of cells destined for neoplastic transformation.

Nassour J, Aguiar LG, Correia A, Schmidt TT, Mainz L, Przetocka S, et al. Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis. Nature 2023;614:767–73.

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