Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis

• Published in: Nature (London) Vol. 614; no. 7949; pp. 767 - 773
• Main Authors: Nassour, Joe, Aguiar, Lucia Gutierrez, Correia, Adriana, Schmidt, Tobias T, Mainz, Laura, Przetocka, Sara, Haggblom, Candy, Tadepalle, Nimesha, Williams, April, Shokhirev, Maxim N, Akincilar, Semih C, Tergaonkar, Vinay, Shadel, Gerald S, Karlseder, Jan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.02.2023; Nature Publishing Group UK
• Subjects: Acids; Adapter proteins; Apoptosis; Autophagy; Cell cycle; Crises; Deoxyribonucleic acid; DNA; DNA - biosynthesis; DNA - genetics; DNA - metabolism; DNA Replication; DNA structure; Epigenetics; Filaments; Genes; Humans; Immune response; Immunity, Innate; Innate immunity; Interferons; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mutation; Neoplasms - genetics; Neoplasms - pathology; Oligomerization; Phosphorylation; Proteins; RNA, Long Noncoding - biosynthesis; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Senescence; Sensors; Signal Transduction; Signaling; Telomerase; Telomere - genetics; Telomere - metabolism; Telomeres; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-05710-8

Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations . However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.