Zup1, also known as Zinc finger-containing ubiquitin peptidase 1 and ZUFSP/C6orf113, is a protein with a unique structure featuring four N-terminal zinc finger domains and a C-terminal deubiquitinase (DUB) domain. It belongs to a distinct DUB family and is involved in multiple important biological pathways. Zup1 is associated with the DNA damage response and plays a crucial role in innate immunity, especially in the mitochondrial antiviral signaling (MAVS) complex, which is essential for host antiviral defense [1,2,3,4,5,6].

In terms of its role in innate immunity, viral infection significantly upregulates Zup1 expression [1]. Mice lacking Zup1 exhibit impaired type I interferon (IFN) production and increased susceptibility to viral infection, as indicated by higher mortality rates [1]. Mechanistically, Zup1 binds to MAVS through its C-terminal domain independent of DUB activity, and uses its zinc finger domains (particularly the third zinc finger) to directly bind viral RNA. This enhances its association with MAVS and promotes 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 [1]. In addition, Zup1 has been shown to be involved in genome stability pathways. It localizes to DNA lesions, selectively cleaves K63-linked polyubiquitin chains, and plays a role in preventing spontaneous DNA damage and promoting cellular survival in response to exogenous DNA damage [2,5].

In conclusion, Zup1 is a multifunctional protein with essential roles in innate immunity against viral infections and in maintaining genome stability. The use of Zup1 knockout mouse models has been instrumental in revealing its role in these biological processes, providing valuable insights into potential therapeutic targets for viral infections and understanding the mechanisms underlying genome stability-related diseases [1,2,5].

References:

1. Hao, Wenyan, Guo, Mengfan, Ji, Xin, Lu, Dan, Yin, Yuxin. . ZUP1 is a key component of the MAVS complex and acts as a protector of host against viral invasion. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 39, e70419. doi:10.1096/fj.202401661RRR. https://pubmed.ncbi.nlm.nih.gov/40095368/

2. Kwasna, Dominika, Abdul Rehman, Syed Arif, Natarajan, Jayaprakash, Gibbs-Seymour, Ian, Kulathu, Yogesh. 2018. Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability. In Molecular cell, 70, 150-164.e6. doi:10.1016/j.molcel.2018.02.023. https://pubmed.ncbi.nlm.nih.gov/29576527/

3. Hermanns, Thomas, Pichlo, Christian, Baumann, Ulrich, Hofmann, Kay. 2022. A structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family. In Nature communications, 13, 401. doi:10.1038/s41467-022-28049-6. https://pubmed.ncbi.nlm.nih.gov/35058438/

4. Hewings, David S, Heideker, Johanna, Ma, Taylur P, Bogyo, Matthew, Wertz, Ingrid E. 2018. Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes. In Nature communications, 9, 1162. doi:10.1038/s41467-018-03511-6. https://pubmed.ncbi.nlm.nih.gov/29563501/

5. Haahr, Peter, Borgermann, Nikoline, Guo, Xiaohu, Sixma, Titia K, Mailand, Niels. 2018. ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability. In Molecular cell, 70, 165-174.e6. doi:10.1016/j.molcel.2018.02.024. https://pubmed.ncbi.nlm.nih.gov/29576528/

6. Hermanns, Thomas, Pichlo, Christian, Woiwode, Ilka, Baumann, Ulrich, Hofmann, Kay. 2018. A family of unconventional deubiquitinases with modular chain specificity determinants. In Nature communications, 9, 799. doi:10.1038/s41467-018-03148-5. https://pubmed.ncbi.nlm.nih.gov/29476094/