ArticleScience advances2026
The accessory adapters FAF1, FAF2, and UBXN7 accelerate proteasomal degradation by increasing prior p97-mediated substrate unfolding.
Article in Science advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.The EMBO journal · 2026Article
- FAF1 cofactor enhances UFD1/NPL4-p97 unfolding efficiency across ubiquitin chain lengths independent of SUMO2.bioRxiv : the preprint server for biology · 2026Article
- Proteomic Analysis Reveals That P97 Inhibitors Induce Ferroptosis in Gastric Cancer AGS Cells.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.Research square · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.bioRxiv : the preprint server for biology · 2026Article
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Authors and funding
7 authors.
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Abstract
The AAA-ATPase VCP/p97 with its adapter Ufd1-Npl4 unfolds ubiquitylated substrate proteins to prepare degradation in the proteasome; however, the function of critical accessory factors remains unclear. Here, we show in the mammalian system that efficient protein degradation in the proteasome requires accessory adapters that boost p97-mediated unfolding likely by positioning Ufd1 for substrate loading. In a reaction that reconstitutes p97-Ufd1-Npl4-mediated unfolding coupled to proteasomal degradation, degradation was inefficient but stimulated by accessory adapters FAF1, FAF2, or UBXN7. Stimulation of proteasomal degradation was largely caused by an increase of p97 unfolding rates, conveyed by a helix-UBX segment in FAF1/2 that tethered the UT3 ubiquitin binding module of Ufd1 to the p97 N-domain. Mutations that abrogated the helix-Ufd1 interaction reduced stimulation of degradation, suggesting that accessory adapters position Ufd1 within the p97 complex to organize proficient substrate loading. Our results define the function of accessory adapters in mammals and highlight the complexity of substrate loading onto p97 for efficient substrate processing.
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