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Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival

Post-translational modifications including protein ubiquitination regulate a plethora of cellular processes in distinct manners. RNA N(6)-methyladenosine is the most abundant post-transcriptional modification on mammalian mRNAs and plays important roles in various physiological and pathological cond...

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Autores principales: Wang, Peipei, Wang, Jing, Yao, Shuxin, Cui, Manman, Cheng, Ying, Liu, Weidong, Gao, Zhuying, Hu, Jin, Zhang, Jinfang, Zhang, Haojian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10424212/
https://www.ncbi.nlm.nih.gov/pubmed/37454738
http://dx.doi.org/10.1016/j.jbc.2023.105055
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author Wang, Peipei
Wang, Jing
Yao, Shuxin
Cui, Manman
Cheng, Ying
Liu, Weidong
Gao, Zhuying
Hu, Jin
Zhang, Jinfang
Zhang, Haojian
author_facet Wang, Peipei
Wang, Jing
Yao, Shuxin
Cui, Manman
Cheng, Ying
Liu, Weidong
Gao, Zhuying
Hu, Jin
Zhang, Jinfang
Zhang, Haojian
author_sort Wang, Peipei
collection PubMed
description Post-translational modifications including protein ubiquitination regulate a plethora of cellular processes in distinct manners. RNA N(6)-methyladenosine is the most abundant post-transcriptional modification on mammalian mRNAs and plays important roles in various physiological and pathological conditions including hematologic malignancies. We previously determined that the RNA N(6)-methyladenosine eraser ALKBH5 is necessary for the maintenance of acute myeloid leukemia (AML) stem cell function, but the post-translational modifications involved in ALKBH5 regulation remain elusive. Here, we show that deubiquitinase ubiquitin-specific peptidase 9X (USP9X) stabilizes ALKBH5 and promotes AML cell survival. Through the use of mass spectrometry as an unbiased approach, we identify USP9X and confirm that it directly binds to ALKBH5. USP9X stabilizes ALKBH5 by removing the K48-linked polyubiquitin chain at K57. Using human myeloid leukemia cells and a murine AML model, we find that genetic knockdown or pharmaceutical inhibition of USP9X inhibits leukemia cell proliferation, induces apoptosis, and delays AML development. Ectopic expression of ALKBH5 partially mediates the function of USP9X in AML. Overall, this study uncovers deubiquitinase USP9X as a key for stabilizing ALKBH5 expression and reveals the important role of USP9X in AML, which provides a promising therapeutic strategy for AML treatment in the clinic.
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spelling pubmed-104242122023-08-15 Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival Wang, Peipei Wang, Jing Yao, Shuxin Cui, Manman Cheng, Ying Liu, Weidong Gao, Zhuying Hu, Jin Zhang, Jinfang Zhang, Haojian J Biol Chem Research Article Post-translational modifications including protein ubiquitination regulate a plethora of cellular processes in distinct manners. RNA N(6)-methyladenosine is the most abundant post-transcriptional modification on mammalian mRNAs and plays important roles in various physiological and pathological conditions including hematologic malignancies. We previously determined that the RNA N(6)-methyladenosine eraser ALKBH5 is necessary for the maintenance of acute myeloid leukemia (AML) stem cell function, but the post-translational modifications involved in ALKBH5 regulation remain elusive. Here, we show that deubiquitinase ubiquitin-specific peptidase 9X (USP9X) stabilizes ALKBH5 and promotes AML cell survival. Through the use of mass spectrometry as an unbiased approach, we identify USP9X and confirm that it directly binds to ALKBH5. USP9X stabilizes ALKBH5 by removing the K48-linked polyubiquitin chain at K57. Using human myeloid leukemia cells and a murine AML model, we find that genetic knockdown or pharmaceutical inhibition of USP9X inhibits leukemia cell proliferation, induces apoptosis, and delays AML development. Ectopic expression of ALKBH5 partially mediates the function of USP9X in AML. Overall, this study uncovers deubiquitinase USP9X as a key for stabilizing ALKBH5 expression and reveals the important role of USP9X in AML, which provides a promising therapeutic strategy for AML treatment in the clinic. American Society for Biochemistry and Molecular Biology 2023-07-15 /pmc/articles/PMC10424212/ /pubmed/37454738 http://dx.doi.org/10.1016/j.jbc.2023.105055 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Wang, Peipei
Wang, Jing
Yao, Shuxin
Cui, Manman
Cheng, Ying
Liu, Weidong
Gao, Zhuying
Hu, Jin
Zhang, Jinfang
Zhang, Haojian
Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival
title Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival
title_full Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival
title_fullStr Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival
title_full_unstemmed Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival
title_short Deubiquitinase USP9X stabilizes RNA m(6)A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival
title_sort deubiquitinase usp9x stabilizes rna m(6)a demethylase alkbh5 and promotes acute myeloid leukemia cell survival
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10424212/
https://www.ncbi.nlm.nih.gov/pubmed/37454738
http://dx.doi.org/10.1016/j.jbc.2023.105055
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