Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis
Abstract Fortilin, a 172-amino acid polypeptide, is a multifunctional protein that interacts with various protein molecules to regulate their functions. Although fortilin has been shown to interact with cytoskeleton proteins such as tubulin and actin, its interactions with the components of adherens...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07399-5 |
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| author | Mari Nakashima Decha Pinkaew Uttariya Pal Fei Miyao Hanna Huynh Lena Tanaka Ken Fujise |
| author_facet | Mari Nakashima Decha Pinkaew Uttariya Pal Fei Miyao Hanna Huynh Lena Tanaka Ken Fujise |
| author_sort | Mari Nakashima |
| collection | DOAJ |
| description | Abstract Fortilin, a 172-amino acid polypeptide, is a multifunctional protein that interacts with various protein molecules to regulate their functions. Although fortilin has been shown to interact with cytoskeleton proteins such as tubulin and actin, its interactions with the components of adherens junctions remained unknown. Using co-immunoprecipitation western blot analyses, the proximity ligation assay, microscale thermophoresis, and biolayer interferometry, we here show that fortilin specifically interacts with CTNNA3 (α-T-catenin), but not with CTNNA1, CTNNA2, or CTNNB. The silencing of fortilin using small interfering RNA (siRNAfortilin) promotes the proteasome-mediated degradation of CTNNA3 in 293T cells. Using both fortilin-deficient THP1 cells and 293T cells that overexpress wild-type (WT), phospho-null (5A), and phospho-mimetic (5D) CTNNA3s, we also show that the absence of fortilin accelerates the phosphorylation of CTNNA3, leading to its ubiquitination and proteasome-mediated degradation. Further, the silencing of CTNNA3 using siRNACTNNA3 causes 293T cells to undergo apoptosis. These data suggest that fortilin guards the cells against apoptosis by positively regulating the pro-survival molecule CTNNA3 by protecting it against phosphorylation, ubiquitination, and proteasome-mediated degradation. |
| format | Article |
| id | doaj-art-e97e448e386f4ca6ad1eeb0a51ca06a0 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-e97e448e386f4ca6ad1eeb0a51ca06a02025-01-05T12:43:09ZengNature PortfolioCommunications Biology2399-36422025-01-018111510.1038/s42003-024-07399-5Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosisMari Nakashima0Decha Pinkaew1Uttariya Pal2Fei Miyao3Hanna Huynh4Lena Tanaka5Ken Fujise6Division of Cardiology, Department of Medicine, University of WashingtonDivision of Cardiology, Department of Medicine, University of WashingtonDivision of Cardiology, Department of Medicine, University of WashingtonDivision of Cardiology, Department of Medicine, University of Texas Medical BranchDivision of Cardiology, Department of Medicine, University of WashingtonDivision of Cardiology, Department of Medicine, University of WashingtonDivision of Cardiology, Department of Medicine, University of WashingtonAbstract Fortilin, a 172-amino acid polypeptide, is a multifunctional protein that interacts with various protein molecules to regulate their functions. Although fortilin has been shown to interact with cytoskeleton proteins such as tubulin and actin, its interactions with the components of adherens junctions remained unknown. Using co-immunoprecipitation western blot analyses, the proximity ligation assay, microscale thermophoresis, and biolayer interferometry, we here show that fortilin specifically interacts with CTNNA3 (α-T-catenin), but not with CTNNA1, CTNNA2, or CTNNB. The silencing of fortilin using small interfering RNA (siRNAfortilin) promotes the proteasome-mediated degradation of CTNNA3 in 293T cells. Using both fortilin-deficient THP1 cells and 293T cells that overexpress wild-type (WT), phospho-null (5A), and phospho-mimetic (5D) CTNNA3s, we also show that the absence of fortilin accelerates the phosphorylation of CTNNA3, leading to its ubiquitination and proteasome-mediated degradation. Further, the silencing of CTNNA3 using siRNACTNNA3 causes 293T cells to undergo apoptosis. These data suggest that fortilin guards the cells against apoptosis by positively regulating the pro-survival molecule CTNNA3 by protecting it against phosphorylation, ubiquitination, and proteasome-mediated degradation.https://doi.org/10.1038/s42003-024-07399-5 |
| spellingShingle | Mari Nakashima Decha Pinkaew Uttariya Pal Fei Miyao Hanna Huynh Lena Tanaka Ken Fujise Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis Communications Biology |
| title | Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis |
| title_full | Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis |
| title_fullStr | Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis |
| title_full_unstemmed | Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis |
| title_short | Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis |
| title_sort | fortilin binds ctnna3 and protects it against phosphorylation ubiquitination and proteasomal degradation to guard cells against apoptosis |
| url | https://doi.org/10.1038/s42003-024-07399-5 |
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