Insight into the scaffolding function of USP18 from a high resolution cryo-EM structure of STAT2-USP18-ISG15 ternary complex
Year: 2026
Type: preprint
Abstract: USP18 is a primary negative regulator of the type I interferon (IFN-I) signaling which regulates hundreds of IFN-stimulated genes for viral protection and anti-cancer immunity. USP18 plays dual roles in the IFN-I signaling: 1) deubiquitinase enzymatic function which cleaves ISG15 from its substrates and 2) scaffolding function through forming a complex with STAT2 to suppress IFN-I signaling. Targeting the scaffolding function of USP18, instead of its enzyme activity, is crucial for reducing cancer cell fitness and boosting anti-tumor immunity. However, the molecular basis of USP18’s scaffolding function remains unclear due to the lack of structural information. Here, using a fusion tag strategy, we captured the transient USP18-STAT2 complex and determined a ternary complex structure of STAT2-USP18-ISG15 at 3.05 Å resolution by cryogenic electron microscopy (cryo-EM) that delineated detailed USP18-STAT2 interactions. Remarkably, the ternary complex impairs USP18’s enzymatic function by STAT2-mediated disruption of its catalytic triad. Structural analysis and mutagenesis identify specific USP18 point mutations, facilitating further investigation into the role of USP18 in IFN-I signaling. Taken together, our findings suggest that USP18’s scaffolding function could present an untapped opportunity for cancer therapy.
Authors: Kevin W. Huynh, Rachel Plumb, David R. Healy, Veronica Jové, Erik C. Ralph, Chiachin Wilson Lee, Heather Wheeler, Kymberly Levine, Zhen Huang, Kimberly Fennell, Richard A. Corpina, Timothy Craig, Paul D. Wes, Paula M Loria, Monica Schenone, Seungil Han, Feng Wang, Huixian Wu, Masaya Yamaguchi
Institution: Pfizer (United States)
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7128705242