HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways
Summary: HUWE1 is a large, enigmatic HECT-domain ubiquitin ligase implicated in the regulation of diverse pathways, including DNA repair, apoptosis, and differentiation. How HUWE1 engages its structurally diverse substrates and how HUWE1 activity is regulated are unknown. Using unbiased quantitative...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-05-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723005077 |
| _version_ | 1797829571207233536 |
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| author | Julie K. Monda Xuezhen Ge Moritz Hunkeler Katherine A. Donovan Michelle W. Ma Cyrus Y. Jin Marilyn Leonard Eric S. Fischer Eric J. Bennett |
| author_facet | Julie K. Monda Xuezhen Ge Moritz Hunkeler Katherine A. Donovan Michelle W. Ma Cyrus Y. Jin Marilyn Leonard Eric S. Fischer Eric J. Bennett |
| author_sort | Julie K. Monda |
| collection | DOAJ |
| description | Summary: HUWE1 is a large, enigmatic HECT-domain ubiquitin ligase implicated in the regulation of diverse pathways, including DNA repair, apoptosis, and differentiation. How HUWE1 engages its structurally diverse substrates and how HUWE1 activity is regulated are unknown. Using unbiased quantitative proteomics, we find that HUWE1 targets substrates in a largely cell-type-specific manner. However, we identify C16orf72/HAPSTR1 as a robust HUWE1 substrate in multiple cell lines. Previously established physical and genetic interactions between HUWE1 and HAPSTR1 suggest that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is required for HUWE1 nuclear localization and nuclear substrate targeting. Nuclear HUWE1 is required for both cell proliferation and modulation of stress signaling pathways, including p53 and nuclear factor κB (NF-κB)-mediated signaling. Combined, our results define a role for HAPSTR1 in gating critical nuclear HUWE1 functions. |
| first_indexed | 2024-04-09T13:22:17Z |
| format | Article |
| id | doaj.art-adc1daeb5c5d4f8581b20f042daa562e |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T13:22:17Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-adc1daeb5c5d4f8581b20f042daa562e2023-05-11T04:23:49ZengElsevierCell Reports2211-12472023-05-01425112496HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathwaysJulie K. Monda0Xuezhen Ge1Moritz Hunkeler2Katherine A. Donovan3Michelle W. Ma4Cyrus Y. Jin5Marilyn Leonard6Eric S. Fischer7Eric J. Bennett8School of Biological Sciences, Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, USASchool of Biological Sciences, Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USASchool of Biological Sciences, Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USASchool of Biological Sciences, Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, USA; Corresponding authorSummary: HUWE1 is a large, enigmatic HECT-domain ubiquitin ligase implicated in the regulation of diverse pathways, including DNA repair, apoptosis, and differentiation. How HUWE1 engages its structurally diverse substrates and how HUWE1 activity is regulated are unknown. Using unbiased quantitative proteomics, we find that HUWE1 targets substrates in a largely cell-type-specific manner. However, we identify C16orf72/HAPSTR1 as a robust HUWE1 substrate in multiple cell lines. Previously established physical and genetic interactions between HUWE1 and HAPSTR1 suggest that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is required for HUWE1 nuclear localization and nuclear substrate targeting. Nuclear HUWE1 is required for both cell proliferation and modulation of stress signaling pathways, including p53 and nuclear factor κB (NF-κB)-mediated signaling. Combined, our results define a role for HAPSTR1 in gating critical nuclear HUWE1 functions.http://www.sciencedirect.com/science/article/pii/S2211124723005077CP: Molecular biologyCP: Cell biology |
| spellingShingle | Julie K. Monda Xuezhen Ge Moritz Hunkeler Katherine A. Donovan Michelle W. Ma Cyrus Y. Jin Marilyn Leonard Eric S. Fischer Eric J. Bennett HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways Cell Reports CP: Molecular biology CP: Cell biology |
| title | HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways |
| title_full | HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways |
| title_fullStr | HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways |
| title_full_unstemmed | HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways |
| title_short | HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways |
| title_sort | hapstr1 localizes huwe1 to the nucleus to limit stress signaling pathways |
| topic | CP: Molecular biology CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723005077 |
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