TSG101 depletion dysregulates mitochondria and PML NBs, triggering MAD2-overexpressing interphase cell death (MOID) through AIFM1-PML-DAXX pathway.

Autor: Xi Y; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Xu R; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Chen S; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Fang J; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Duan X; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Zhang Y; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Zhong G; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., He Z; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Guo Y; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Li X; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Tao W; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Li Y; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Li Y; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China., Fang L; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China. njfanglei@nju.edu.cn., Niikura Y; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China. niikura@nju.edu.cn.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210032, China. niikura@nju.edu.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Nov 17; Vol. 15 (11), pp. 838. Date of Electronic Publication: 2024 Nov 17.
DOI: 10.1038/s41419-024-07229-w
Abstrakt: Overexpression of mitotic arrest deficiency 2 (MAD2/MAD2L1), a pivotal component of the spindle assembly checkpoint (SAC), resulted in many types of cancer. Here we show that the depletion of tumor susceptibility gene 101 (TSG101), causes synthetic dosage lethality (SDL) in MAD2-overexpressing cells, and we term this cell death MAD2-overexpressing interphase cell death (MOID). The induction of MOID depends on PML and DAXX mediating mitochondrial AIFM1-release. MAD2, TSG101, and AIF-PML-DAXX axis regulate mitochondria, PML nuclear bodies (NBs), and autophagy with close inter-dependent protein stability in survival cells. Loss of C-terminal phosphorylation(s) of TSG101 and closed (C-)MAD2-overexpression contribute to induce MOID. In survival cells, both MAD2 and TSG101 localize at PML NBs in interphase, and TSG101 Y390 phosphorylation is required for localization of TSG101 to PML NBs. PML release from PML NBs through PML deSUMOylation contributes to induce MOID. The post-transcriptional/translational cell death machinery and the non-canonical transcriptional regulation are intricately linked to MOID, and ER-MAM, may serve as a crucial intersection for MOID signaling.
Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate All methods were performed in accordance with the relevant guidelines and regulations. The Ethics Committee at Model Animal Research Center of Nanjing University approved the animal protocols used in this study (reference/registration number: IACUC-D2108001). No human research participants are involved in this study.
(© 2024. The Author(s).)
Databáze: MEDLINE
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