Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome-Reference-Cited by-同舟云学术

Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome

Published:2024-01-26 Issue:4 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Pandey Abhimanu¹^ORCID,Shen Cheng¹^ORCID,Feng Shouya¹,Enosi Tuipulotu Daniel¹^ORCID,Ngo Chinh¹,Liu Cheng²³⁴,Kurera Melan¹^ORCID,Mathur Anukriti¹,Venkataraman Shweta¹,Zhang Jing¹,Talaulikar Dipti¹⁵⁶⁷^ORCID,Song Renhua⁸⁹^ORCID,Wong Justin J.-L.⁸⁹^ORCID,Teoh Narci¹⁰,Kaakoush Nadeem O.¹¹^ORCID,Man Si Ming¹^ORCID

Affiliation:

1. Division of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.

2. Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.

3. School of Medicine, University of Queensland, Herston, Australia.

4. Mater Pathology, Mater Hospital, South Brisbane, Australia.

5. Haematology Translational Research Unit, ACT Pathology, Canberra Health Services, Canberra, Australian Capital Territory, Australia.

6. Department of Human Genomics, ACT Pathology, Canberra, Australian Capital Territory, Australia.

7. School of Medicine and Psychology, College of Health and Medicine, The Australian National University, Canberra, Australia.

8. Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown 2050, Australia.

9. Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia.

10. Gastroenterology and Hepatology Unit, The Australian National University Medical School at The Canberra Hospital, The Australian National University, Canberra, Australia.

11. School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia.

Abstract

The innate immune response contributes to the development or attenuation of acute and chronic diseases, including cancer. Microbial DNA and mislocalized DNA from damaged host cells can activate different host responses that shape disease outcomes. Here, we show that mice and humans lacking a single allele of the DNA repair protein Ku70 had increased susceptibility to the development of intestinal cancer. Mechanistically, Ku70 translocates from the nucleus into the cytoplasm where it binds to cytosolic DNA and interacts with the GTPase Ras and the kinase Raf, forming a tripartite protein complex and docking at Rab5 + Rab7 + early-late endosomes. This Ku70-Ras-Raf signalosome activates the MEK-ERK pathways, leading to impaired activation of cell cycle proteins Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. We also identified the domains of Ku70, Ras, and Raf involved in activating the Ku70 signaling pathway. Therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adh3409

Reference118 articles.

1. Pattern Recognition Receptors and Inflammation

2. Context-dependent functions of pattern recognition receptors in cancer

3. Cytosolic DNA Sensing in Organismal Tumor Control

4. Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids

5. Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer