The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP
The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous reg...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/92409 |
| _version_ | 1797670760878178304 |
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| author | Maria Körner Susanne R Meyer Gabriella Marincola Maximilian J Kern Clemens Grimm Christina Schuelein-Voelk Utz Fischer Kay Hofmann Alexander Buchberger |
| author_facet | Maria Körner Susanne R Meyer Gabriella Marincola Maximilian J Kern Clemens Grimm Christina Schuelein-Voelk Utz Fischer Kay Hofmann Alexander Buchberger |
| author_sort | Maria Körner |
| collection | DOAJ |
| description | The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97–cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions. |
| first_indexed | 2024-03-11T21:04:15Z |
| format | Article |
| id | doaj.art-088885aee7b845c49c72985154a87b7b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T21:04:15Z |
| publishDate | 2023-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-088885aee7b845c49c72985154a87b7b2023-09-29T14:25:58ZengeLife Sciences Publications LtdeLife2050-084X2023-09-011210.7554/eLife.92409The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCPMaria Körner0Susanne R Meyer1Gabriella Marincola2https://orcid.org/0000-0001-9227-6554Maximilian J Kern3Clemens Grimm4Christina Schuelein-Voelk5Utz Fischer6https://orcid.org/0000-0002-1465-6591Kay Hofmann7https://orcid.org/0000-0002-2289-9083Alexander Buchberger8https://orcid.org/0000-0002-2836-0820University of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, GermanyUniversity of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, GermanyUniversity of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, GermanyDepartment of Molecular Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyUniversity of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, GermanyCore Unit High-Content Microscopy, Biocenter, University of Würzburg, Würzburg, GermanyUniversity of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, GermanyInstitute of Genetics, University of Cologne, Cologne, GermanyUniversity of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, GermanyThe ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97–cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions.https://elifesciences.org/articles/92409p97 VCP Cdc48ubiquitin proteasome systemnuclear importDNA damage repairFAM104A FLJ14775FAM104B FLJ20434 CXorf44 |
| spellingShingle | Maria Körner Susanne R Meyer Gabriella Marincola Maximilian J Kern Clemens Grimm Christina Schuelein-Voelk Utz Fischer Kay Hofmann Alexander Buchberger The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP eLife p97 VCP Cdc48 ubiquitin proteasome system nuclear import DNA damage repair FAM104A FLJ14775 FAM104B FLJ20434 CXorf44 |
| title | The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP |
| title_full | The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP |
| title_fullStr | The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP |
| title_full_unstemmed | The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP |
| title_short | The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP |
| title_sort | fam104 proteins vcf1 2 promote the nuclear localization of p97 vcp |
| topic | p97 VCP Cdc48 ubiquitin proteasome system nuclear import DNA damage repair FAM104A FLJ14775 FAM104B FLJ20434 CXorf44 |
| url | https://elifesciences.org/articles/92409 |
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