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...

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Published in:eLife 2023-09, Vol.12
Main Authors: Körner, Maria, Meyer, Susanne R, Marincola, Gabriella, Kern, Maximilian J, Grimm, Clemens, Schuelein-Voelk, Christina, Fischer, Utz, Hofmann, Kay, Buchberger, Alexander
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Biochemistry and Chemical Biology
Cell Biology
DNA damage
DNA damage repair
DNA repair
FAM104A FLJ14775
FAM104B FLJ20434 CXorf44
Homeostasis
Localization
Neuromuscular diseases
nuclear import
Nuclear transport
p97 VCP Cdc48
Protein structure
Proteins
Quality control
ubiquitin proteasome system
Yeast
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Summary: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 V CP nuclear c ofactor f amily 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.92409