SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction
The NFκB/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NFκB2/p100 precursor has been characterized as the fourth IκB type of suppressor for NFκB. However, the molecular mechanism(s) underlying...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712001155 |
| _version_ | 1828737786821214208 |
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| author | Hidefumi Fukushima Akinobu Matsumoto Hiroyuki Inuzuka Bo Zhai Alan W. Lau Lixin Wan Daming Gao Shavali Shaik Min Yuan Steven P. Gygi Eijiro Jimi John M. Asara Keiko Nakayama Keiichi I. Nakayama Wenyi Wei |
| author_facet | Hidefumi Fukushima Akinobu Matsumoto Hiroyuki Inuzuka Bo Zhai Alan W. Lau Lixin Wan Daming Gao Shavali Shaik Min Yuan Steven P. Gygi Eijiro Jimi John M. Asara Keiko Nakayama Keiichi I. Nakayama Wenyi Wei |
| author_sort | Hidefumi Fukushima |
| collection | DOAJ |
| description | The NFκB/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NFκB2/p100 precursor has been characterized as the fourth IκB type of suppressor for NFκB. However, the molecular mechanism(s) underlying regulated destruction of NFκB2 remains largely unknown. Here, we report that, unlike other IκBs, ubiquitination and destruction of NFκB2 are governed by SCFFbw7 in a GSK3-dependent manner. In Fbw7−/− cells, elevated expression of NFκB2/p100 leads to a subsequent reduction in NFκB signaling pathways and elevated sensitivity to TNFα-induced cell death. Reintroducing wild-type Fbw7, but not disease-derived mutant forms of Fbw7, rescues NFκB activity. Furthermore, T cell-specific depletion of Fbw7 also leads to reduced NFκB activity and perturbed T cell differentiation. Therefore, our work identifies Fbw7 as a physiological E3 ligase controlling NFκB2′s stability. It further implicates that Fbw7 might exert its tumor-suppressor function by regulating NFκB activity. |
| first_indexed | 2024-04-12T23:51:09Z |
| format | Article |
| id | doaj.art-30210488fb644562aed2f6b37331edb5 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T23:51:09Z |
| publishDate | 2012-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-30210488fb644562aed2f6b37331edb52022-12-22T03:11:42ZengElsevierCell Reports2211-12472012-05-011543444310.1016/j.celrep.2012.04.002SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and DestructionHidefumi Fukushima0Akinobu Matsumoto1Hiroyuki Inuzuka2Bo Zhai3Alan W. Lau4Lixin Wan5Daming Gao6Shavali Shaik7Min Yuan8Steven P. Gygi9Eijiro Jimi10John M. Asara11Keiko Nakayama12Keiichi I. Nakayama13Wenyi Wei14Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, JapanDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Cell Biology, Harvard Medical School, Boston, MA 02115, USADepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Cell Biology, Harvard Medical School, Boston, MA 02115, USACenter for Oral Biological Research, Kyushu Dental College, Fukuoka 803-8508, JapanDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADivision of Developmental Genetics, Tohoku University Graduate School of Medicine, Aoba-Ku, Sendai 980-8575, JapanDepartment of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, JapanDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USAThe NFκB/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NFκB2/p100 precursor has been characterized as the fourth IκB type of suppressor for NFκB. However, the molecular mechanism(s) underlying regulated destruction of NFκB2 remains largely unknown. Here, we report that, unlike other IκBs, ubiquitination and destruction of NFκB2 are governed by SCFFbw7 in a GSK3-dependent manner. In Fbw7−/− cells, elevated expression of NFκB2/p100 leads to a subsequent reduction in NFκB signaling pathways and elevated sensitivity to TNFα-induced cell death. Reintroducing wild-type Fbw7, but not disease-derived mutant forms of Fbw7, rescues NFκB activity. Furthermore, T cell-specific depletion of Fbw7 also leads to reduced NFκB activity and perturbed T cell differentiation. Therefore, our work identifies Fbw7 as a physiological E3 ligase controlling NFκB2′s stability. It further implicates that Fbw7 might exert its tumor-suppressor function by regulating NFκB activity.http://www.sciencedirect.com/science/article/pii/S2211124712001155 |
| spellingShingle | Hidefumi Fukushima Akinobu Matsumoto Hiroyuki Inuzuka Bo Zhai Alan W. Lau Lixin Wan Daming Gao Shavali Shaik Min Yuan Steven P. Gygi Eijiro Jimi John M. Asara Keiko Nakayama Keiichi I. Nakayama Wenyi Wei SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction Cell Reports |
| title | SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction |
| title_full | SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction |
| title_fullStr | SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction |
| title_full_unstemmed | SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction |
| title_short | SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction |
| title_sort | scffbw7 modulates the nfκb signaling pathway by targeting nfκb2 for ubiquitination and destruction |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712001155 |
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