Cargando…

Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis

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 telome...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9946831/
https://www.ncbi.nlm.nih.gov/pubmed/36755096
http://dx.doi.org/10.1038/s41586-023-05710-8
_version_ 1784892418452094976
author 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
author_facet 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
author_sort Nassour, Joe
collection PubMed
description 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(1,2). 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.
format Online
Article
Text
id pubmed-9946831
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-99468312023-02-24 Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis 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 Nature Article 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(1,2). 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. Nature Publishing Group UK 2023-02-08 2023 /pmc/articles/PMC9946831/ /pubmed/36755096 http://dx.doi.org/10.1038/s41586-023-05710-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
title Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
title_full Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
title_fullStr Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
title_full_unstemmed Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
title_short Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
title_sort telomere-to-mitochondria signalling by zbp1 mediates replicative crisis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9946831/
https://www.ncbi.nlm.nih.gov/pubmed/36755096
http://dx.doi.org/10.1038/s41586-023-05710-8
work_keys_str_mv AT nassourjoe telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT aguiarluciagutierrez telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT correiaadriana telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT schmidttobiast telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT mainzlaura telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT przetockasara telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT haggblomcandy telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT tadepallenimesha telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT williamsapril telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT shokhirevmaximn telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT akincilarsemihc telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT tergaonkarvinay telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT shadelgeralds telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis
AT karlsederjan telomeretomitochondriasignallingbyzbp1mediatesreplicativecrisis