BAP1 controls mesenchymal stem cell migration by inhibiting the ERK signaling pathway
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Due to their stem-like characteristics and immunosuppressiveproperties, Mesenchymal stem cells (MSCs) offer remarkable potential in regenerative medicine. Much effort has been devotedto enhancing the efficacy of MSC therapy by enhancing MSCmigration. In this study, we identified deubiquitinase BRCA1-associated protein 1 (BAP1) as an inhibitor of MSC migration. Using deubiquitinase siRNA library screening based on an invitro wound healing assay, we found that silencing BAP1 significantly augmented MSC migration. Conversely, BAP1 overexpression reduced the migration and invasion capabilities ofMSCs. BAP1 depletion in MSCs upregulates ERK phosphorylation, thereby increasing the expression of the migration factor,osteopontin. Further examination revealed that BAP1 interactswith phosphorylated ERK1/2, deubiquitinating their ubiquitins,and thus attenuating the ERK signaling pathway. Overall, ourstudy highlights the critical role of BAP1 in regulating MSC migration through its deubiquitinase activity, and suggests a novelapproach to improve the therapeutic potential of MSCs in regenerative medicine.
Abstract
Due to their stem-like characteristics and immunosuppressiveproperties, Mesenchymal stem cells (MSCs) offer remarkable potential in regenerative medicine. Much effort has been devotedto enhancing the efficacy of MSC therapy by enhancing MSCmigration. In this study, we identified deubiquitinase BRCA1-associated protein 1 (BAP1) as an inhibitor of MSC migration. Using deubiquitinase siRNA library screening based on an invitro wound healing assay, we found that silencing BAP1 significantly augmented MSC migration. Conversely, BAP1 overexpression reduced the migration and invasion capabilities ofMSCs. BAP1 depletion in MSCs upregulates ERK phosphorylation, thereby increasing the expression of the migration factor,osteopontin. Further examination revealed that BAP1 interactswith phosphorylated ERK1/2, deubiquitinating their ubiquitins,and thus attenuating the ERK signaling pathway. Overall, ourstudy highlights the critical role of BAP1 in regulating MSC migration through its deubiquitinase activity, and suggests a novelapproach to improve the therapeutic potential of MSCs in regenerative medicine.
참고문헌 (32)
- Naji A, "Biological functions of mesenchymal stem cells and clinical implications", Cell Mol Life Sci, 76, pp.3323~3348 (2019)
- Nauta AJ, "Immunomodulatory properties of mesenchymal stromal cells", Blood, 110, pp.3499~3506 (2007)
- Francois M, "Human MSC suppression correlates with cytokine induction of indoleamine 2, 3-dioxygenase and bystander M2 macrophage differentiation", Mol Ther, 20, pp.187~195 (2012)
- Bernardo ME, "Mesenchymal stromal cells : sensors and switchers of inflammation", Cell Stem Cell, 13, pp.392~402 (2013)
- Prockop DJ, "Concise review : two negative feedback loops place mesenchymal stem", stromal cells at the center of early regulators of inflammation, 2013, pp.31, 2042~2046
- Ankrum J, "Mesenchymal stem cell therapy : two steps forward, one step back", Trends Mol Med, 16, pp.203~209 (2010)
- Nitzsche F, "Concise review : MSC adhesion cascadeinsights into homing and transendothelial migration", Stem Cells, 35, pp.1446~1460 (2017)
- Mun JY, "Minicircle microporation-based non-viral gene delivery improved the targeting of mesenchymal stem cells to an injury site", Biomaterials, 101, pp.310~320 (2016)
- Fu X, "Mesenchymal stem cell migration and tissue repair", Cells, 8, pp.784~ (2019)
- Swatek KN, "Ubiquitin modifications", Cell Res, 26, pp.399~422 (2016)
- Mevissen TET, "Mechanisms of deubiquitinase specificity and regulation", Annu Rev Biochem, 86, pp.159~192 (2017)
- Masclef L, "Roles and mechanisms of BAP1 deubiquitinase in tumor suppression", Cell Death Differ, 28, pp.606~625 (2021)
- Machida YJ, "The deubiquitinating enzyme BAP1regulates cell growth via interaction with HCF-1", J Biol Chem, 284, pp.34179~34188 (2009)
- Ruan HB, "O-GlcNAc transferase", host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1alpha stability, 2012, pp.16, 226~237
- Qin J, "BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5", Nat Commun, 6, pp.8471~ (2015)
- Bononi A, "BAP1regulates IP3R3-mediated Ca(2+)flux to mitochondria suppressing cell transformation", Nature, 546, pp.549~553 (2017)
- Yu L, "BAP1regulation of the key adaptor protein NCoR1 is critical for gamma-globin gene repression", Genes Dev, 32, pp.1537~1549 (2018)
- Lee HS, "BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress", Biochem J, 476, pp.3053~3066 (2019)
- Cha EB, "Antibodysecreting macrophages generated using CpG-free plasmid eliminate tumor cells through antibody-dependent cellular phagocytosis", BMB Rep, 53, pp.442~447 (2020)
- Payne DM, "Identification of the regulatory phosphorylation sites in pp42", mitogen-activated protein kinase(MAP kinase), 1991, pp.10, 885~892
- Haystead TA, "Ordered phosphorylation of p42mapk by MAP kinase kinase", FEBS Lett, 306, pp.17~22 (1992)
- Park CM, "BAP1 functions as a tumor promoter in prostate cancer cells through EMT regulation", Genet Mol Biol, 43, pp.e20190328~ (2020)
- Hu D, "Integrated analysis of anti-tumor roles of BAP1 in osteosarcoma", Front Oncol, 12, pp.973914~ (2022)
- Shen C, "BRCA1-associated protein 1 deficiency in lung adenocarcinoma predicts poor outcome and increased tumor invasion", BMC Cancer, 16, pp.670~ (2016)
- Kwon J, "BAP1 as a guardian of genome stability : implications in human cancer", Exp Mol Med, 55, pp.745~754 (2023)
- Perkail S, "BAP1is a haploinsufficient tumor suppressor linking chronic pancreatitis to pancreatic cancer in mice", Nat Commun, 11, pp.3018~ (2020)
- Perez-Garcia V, "BAP1", ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion, 2021, pp.10, e63254~
- Zhu G, "TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination", Nat Cell Biol, 23, pp.978~991 (2021)
- Barbour H, "An inventory of crosstalk between ubiquitination and other post-translational modifications in orchestrating cellular processes", iScience, 26, pp.106276~ (2023)
- Zhou Y, "The kinase CK1varepsilon controls the antiviral immune response by phosphorylating the signaling adaptor TRAF3", Nat Immunol, 17, pp.397~405 (2016)
- Seo J, "K6 linked polyubiquitylation of FADD by CHIP prevents death inducing signaling complex formation suppressing cell death", Oncogene, 37, pp.4994~5006 (2018)
- Seo J, "CHIP controls necroptosis through ubiquitylation-and lysosome-dependent degradation of RIPK3", Nat Cell Biol, 18, pp.291~302 (2016)