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Last update 08 May 2025

ZUP1

Last update 08 May 2025

Basic Info

Synonyms

C6orf113, dJ412I7.3, DUB

+ [6]

Introduction

Deubiquitinase with endodeubiquitinase activity that specifically interacts with and cleaves 'Lys-63'-linked long polyubiquitin chains. Shows only weak activity against 'Lys-11' and 'Lys-48'-linked chains (PubMed:29476094, PubMed:29563501, PubMed:29576528). Plays an important role in genome stability pathways, functioning to prevent spontaneous DNA damage and also promote cellular survival in response to exogenous DNA damage (PubMed:29576527, PubMed:29576528). Modulates the ubiquitination status of replication protein A (RPA) complex proteins in response to replication stress (PubMed:29563501).

Drugs associated with ZUP1

IMP-2373

Target

ZUP1

Mechanism

DUB modulators

Active Org.

Pfizer Inc.

Originator Org.

Pfizer Inc.

Active Indication

Inflammation [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

DUB inhibitor (Mission Therapeutics/Pfizer)

Target

ZUP1

Mechanism

DUB inhibitors

Active Org.

Pfizer Inc. [+1]

Originator Org.

MISSION Therapeutics Ltd.

Active Indication-

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ZUP1

100 Translational Medicine associated with ZUP1

0 Patents (Medical) associated with ZUP1

Literatures (Medical) associated with ZUP1

31 Mar 2025·The FASEB Journal

ZUP1 is a key component of the MAVS complex and acts as a protector of host against viral invasion

Article

Author: Feng, Jiawen ; Zhao, Xuyang ; Hao, Wenyan ; Guo, Mengfan ; Zhu, Minglu ; Wang, Guangxi ; Jin, Yan ; Lu, Dan ; Ji, Xin ; Yin, Yuxin

AbstractZinc finger‐containing ubiquitin peptidase 1 (ZUP1) is a protein characterized by four N‐terminal zinc finger domains and a C‐terminal deubiquitinase (DUB) domain. While it is associated with the DNA damage response, the role of ZUP1 in innate immunity remains unclear. Here, we identify ZUP1 as a crucial component of the mitochondrial antiviral signaling (MAVS) complex, essential for host antiviral defense. We show that viral infection significantly upregulates ZUP1 expression, and mice lacking ZUP1 exhibit impaired type I interferon (IFN) production and increased susceptibility to viral infection, as evidenced by higher mortality rates. This underscores the protective role of ZUP1 in host immunity. Mechanistically, ZUP1 binds to MAVS through its C‐terminal domain independently of DUB activity. Instead, ZUP1 utilizes its zinc finger domains, particularly the third zinc finger, to directly bind viral RNA. This interaction enhances the association of ZUP1 with MAVS and promotes its aggregation on mitochondria during viral infection. ZUP1 also interacts with TBK1 and NEMO within the MAVS complex, facilitating IRF3 activation and type I IFN production. These findings establish ZUP1 as a zinc finger‐containing regulator that amplifies MAVS‐dependent antiviral immunity, linking viral RNA recognition to downstream signaling and highlighting potential targets for therapeutic intervention against viral infections.

01 Apr 2024·International Immunopharmacology

MAVS promotes interferon signaling in RNA virus infection by ZUFSP-mediated chromatin regulation

Article

Author: Li, Siji ; Li, Tongyu

Mitochondria serve as a platform for innate immune signaling transduction, and mitochondrial antiviral signaling protein (MAVS) is essential for interferon-β (IFN-β) production and innate antiviral immunity against RNA viruses. Here, we identified zinc finger-containing ubiquitin peptidase 1 (ZUFSP/ZUP1) as a MAVS-interacting protein by using proximity-based labeling technology in HEK293T and found it could act as a positive regulator of the retinoic acid-inducible gene-I (RIG-I)-like receptors(RLRs), including RIG-I and interferon-induced helicase C domain-containing protein 1 (MDA5). ZUFSP deficiency markedly inhibited RNA virus-triggered induction of downstream antiviral genes, and Zufsp-deficient mice were more susceptible to RNA virus infection. After RNA virus infection,ZUFSP was translocated from cytoplasm to nucleus and interacted with chromatin remodeling complex to facilitate the opening of IFN-stimulated gene (ISG) loci for transcription. This study provides a critical mechanistic basis for MAVS-regulated chromatin remodeling to promote interferon signaling.

01 Apr 2022·Combinatorial Chemistry & High Throughput ScreeningQ4 · MEDICINE

Probing Protein-protein Interactions and Druggable Site Identification: Mechanistic Binding Events Between Ubiquitin and Zinc Finger with UFM1-specific Peptidase Domain Protein (ZUFSP)

Q4 · MEDICINE

Article

Author: Elrashedy, Ahmed A ; Soremekun, Opeyemi S. ; Ajadi, Mary B. ; Soliman, Mahmoud E.S. ; Olotu, Fisayo A. ; Kumalo, Hezekiel M.

Background:Deubiquitinating enzymes (DUBs) protein family have been implicated in some deregulated pathways involved in carcinogenesis such as cell cycle, gene expression, and DNA damage response (DDR). Zinc finger with UFM1-specific peptidase domain protein (ZUFSP) is one of the recently discovered members of the DUBsObjectives:To identify and cross validate the ZUFSP binding site using the bioinformatic tools including SiteMap & Metapocket respectively. To understand the molecular basis of complementary ZUFSP-Ub interaction and associated structural events using MD SimulationMethods:In this study, four binding pockets were predicted, characterized, and cross-validated based on physiochemical features such as site score, druggability score, site volume, and site size. Also, Molecular dynamics simulation technique was employed to determine the impact of ubiquitin-binding on ZUFSPResults:Site 1 with a site score 1.065, Size 102, D scores 1.00, and size volume 261 was predicted to be the most druggable site. Structural studies revealed that upon ubiquitin-binding, the motional movement of ZUFSP was reduced when compared to the unbound ZUFSP. Also, the ZUFSP helical arm (ZHA) domain orient in such a way that it moves closer to the Ub, this orientation enables the formation of a UBD which is very peculiar to ZUFSP.Conclusion:The impact of ubiquitin on ZUFSP movement and the characterization of its predicted druggable site can be targeted in the development of therapeutics

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ZUP1

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