A UBH-UBX module amplifies p97/VCP’s unfolding power to facilitate protein extraction and degradation

Xin-Yu Huo, Di Liu, Rong Zou, Zhao-Peng Li, Yunxia Li, Lifeng Pan, Yaoyang Zhang and Zai-Rong Zhang ()
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Xin-Yu Huo: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry
Di Liu: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry
Rong Zou: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry
Zhao-Peng Li: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry
Yunxia Li: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry
Lifeng Pan: Chinese Academy of Sciences, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry
Yaoyang Zhang: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry
Zai-Rong Zhang: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The p97-UFD1L-NPLOC4 ATPase unfolds numerous proteins for proteasomal degradation, but whether it suffices to pull proteins out of lipid bilayer remains unclear. Here, we identify a conserved ubiquitin-binding helix (UBH) in many UBX-containing p97 adapters, including FAF2, across yeast, plants, and metazoans. The UBH-UBX substantially facilitates the engagement of ubiquitinated substrates with p97-UFD1L-NPLOC4, and enhances p97 motor’s working ATPase and unfolding activities by approximately twofold. Using purified p97-UFD1L-NPLOC4-FAF2UBH-UBX, we reconstitute membrane protein extraction from the ER and mitochondria, establishing p97-UFD1L-NPLOC4-FAF2 (p97-UNF) as a power-enhanced unfoldase. Deleting UBH or disrupting UBH-ubiquitin interaction impairs substrate targeting, reduces p97-UNF’s working ATPase and unfolding activities, and abolishes membrane protein extraction and degradation. We propose that UBH-UBX module amplifies p97’s mechanical output power, enabling the removal of challenging substrates from large assemblies and ensuring rapid responses to protein misfolding or regulatory signals in diverse physiological processes.

Date: 2025
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DOI: 10.1038/s41467-025-65166-4

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