Disrupted autophagy overactivates TBK1 and results in mitotic defects promoting chromosomal instability.
| Title: | Disrupted autophagy overactivates TBK1 and results in mitotic defects promoting chromosomal instability. |
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| Authors: | Paul S; Graduate Program in Biomedical and Veterinary Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.; Tomsick PL; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Milner JP; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Biswas SR; Translational Biology, Medicine, and Health Graduate Program, Virginia Polytechnic Institute and State University, Roanoke, VA, USA.; Brindley S; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; DeFoor N; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Zavar L; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Wright G; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Soto Y; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Pickrell AM; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. |
| Source: | Autophagy [Autophagy] 2026 Apr; Vol. 22 (4), pp. 795-808. Date of Electronic Publication: 2026 Jan 22. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101265188 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8635 (Electronic) Linking ISSN: 15548627 NLM ISO Abbreviation: Autophagy Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2015- : Philadelphia, PA : Taylor & Francis; Original Publication: Georgetown, TX : Landes Bioscience, 2005- |
| MeSH Terms: | Chromosomal Instability*/genetics ; Autophagy*/genetics ; Autophagy*/physiology ; Mitosis*/genetics ; Protein Serine-Threonine Kinases*/metabolism; Centrosome/metabolism ; Autophagy-Related Proteins/metabolism ; Membrane Proteins/metabolism ; Humans ; HeLa Cells |
| Abstract: | Micronuclei are formed during cell division when acentric fragments or lagging chromosomes cannot be incorporated into the primary nucleus. Macroautophagy/autophagy may reduce chromosomal instability (CIN) by clearing isolated, atypical micronuclei. Other studies implicate that the loss of autophagy disrupts DNA repair pathways. However, whether aberrant mitosis contributing to CIN occurs when autophagy is inhibited has yet to be evaluated. We found impaired autophagy initiation contributes to CIN and facilitates the formation of micronuclei and other abnormal nuclear phenotypes either by genetic or pharmacological manipulation in multiple cell lines. We also found that loss of the integral autophagy protein ATG9A resulted in various types of mitotic errors that can contribute to the formation of micronuclei. ATG9A also localizes to centrosomes and midbody during cell division. Autophagy inhibition causes the overactivation and mislocalization of TBK1 (TANK binding kinase 1) into cytoplasmic, punctate structures that colocalize with SQSTM1/p62. This overactivation interferes with its function in cell division as a mitotic kinase and its role at the centrosome. These results indicate that loss of autophagy contributes to genomic instability from multiple angles, one of which being aberrant cell division. |
| Contributed Indexing: | Keywords: ATG9A; TBK1; cell division; chromosomal instability; micronucleation; mitosis |
| Substance Nomenclature: | EC 2.7.11.1 (Protein Serine-Threonine Kinases); EC 2.7.11.1 (TBK1 protein, human); 0 (Autophagy-Related Proteins); 0 (Membrane Proteins) |
| Entry Date(s): | Date Created: 20260116 Date Completed: 20260325 Latest Revision: 20260328 |
| Update Code: | 20260328 |
| PubMed Central ID: | PMC13020882 |
| DOI: | 10.1080/15548627.2026.2617844 |
| PMID: | 41543010 |
| Database: | MEDLINE |
Journal Article