| Structural highlights
Function
VCIP1_HUMAN Deubiquitinating enzyme involved in DNA repair and reassembly of the Golgi apparatus and the endoplasmic reticulum following mitosis (PubMed:32649882). Necessary for VCP-mediated reassembly of Golgi stacks after mitosis (By similarity). Plays a role in VCP-mediated formation of transitional endoplasmic reticulum (tER) (By similarity). Mediates dissociation of the ternary complex containing STX5A, NSFL1C and VCP (By similarity). Also involved in DNA repair following phosphorylation by ATM or ATR: acts by catalyzing deubiquitination of SPRTN, thereby promoting SPRTN recruitment to chromatin and subsequent proteolytic cleavage of covalent DNA-protein cross-links (DPCs) (PubMed:32649882). Hydrolyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitin chains (PubMed:23827681).[UniProtKB:Q8CF97][1] [2] (Microbial infection) Regulates the duration of C.botulinum neurotoxin type A (BoNT/A) intoxication by catalyzing deubiquitination of Botulinum neurotoxin A light chain (LC), thereby preventing LC degradation by the proteasome, and accelerating botulinum neurotoxin intoxication in patients.[3]
Publication Abstract from PubMed
VCP/p97 regulates a wide range of cellular processes, including post-mitotic Golgi reassembly. In this context, VCP is assisted by p47, an adapter protein, and VCPIP1, a deubiquitylase (DUB). However, how they organize into a functional ternary complex to promote Golgi assembly remains unknown. Here, we use cryo-EM to characterize both VCP-VCPIP1 and VCP-VCPIP1-p47 complexes. We show that VCPIP1 engages VCP through two interfaces: one involving the N-domain of VCP and the UBX domain of VCPIP1, and the other involving the VCP D2 domains and a region of VCPIP1 we refer to as VCPID. The p47 UBX domain competitively binds to the VCP N-domain, while not affecting VCPID binding. We show that VCPID is critical for VCP-mediated enhancement of DUB activity and proper Golgi assembly. The ternary structure along with biochemical and cellular data provides new insights into the complex interplay of VCP with its co-factors.
Structural basis of VCP-VCPIP1-p47 ternary complex in Golgi maintenance.,Shah B, Hunkeler M, Bratt A, Yue H, Jaen Maisonet I, Fischer ES, Buhrlage SJ Nat Commun. 2025 Aug 28;16(1):8025. doi: 10.1038/s41467-025-63161-3. PMID:40877265[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM, Ovaa H, Komander D. OTU Deubiquitinases Reveal Mechanisms of Linkage Specificity and Enable Ubiquitin Chain Restriction Analysis. Cell. 2013 Jul 3;154(1):169-84. doi: 10.1016/j.cell.2013.05.046. PMID:23827681 doi:10.1016/j.cell.2013.05.046
- ↑ Huang J, Zhou Q, Gao M, Nowsheen S, Zhao F, Kim W, Zhu Q, Kojima Y, Yin P, Zhang Y, Guo G, Tu X, Deng M, Luo K, Qin B, Machida Y, Lou Z. Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging. Mol Cell. 2020 Sep 3;79(5):824-835.e5. PMID:32649882 doi:10.1016/j.molcel.2020.06.027
- ↑ Tsai YC, Kotiya A, Kiris E, Yang M, Bavari S, Tessarollo L, Oyler GA, Weissman AM. Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication. Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5158-E5166. PMID:28584101 doi:10.1073/pnas.1621076114
- ↑ Shah B, Hunkeler M, Bratt A, Yue H, Jaen Maisonet I, Fischer ES, Buhrlage SJ. Structural basis of VCP-VCPIP1-p47 ternary complex in Golgi maintenance. Nat Commun. 2025 Aug 28;16(1):8025. PMID:40877265 doi:10.1038/s41467-025-63161-3
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