Type I interferon regulation by USP18 is a key vulnerability in cancer
Veronica Jové,
Heather Wheeler,
Chiachin Wilson Lee,
David R. Healy,
Kymberly Levine,
Erik C. Ralph,
Masaya Yamaguchi,
Ziyue Karen Jiang,
Edward Cabral,
Yingrong Xu,
Jeffrey Stock,
Bing Yang,
Anand Giddabasappa,
Paula Loria,
Agustin Casimiro-Garcia,
Benedikt M. Kessler,
Adán Pinto-Fernández,
Véronique Frattini,
Paul D. Wes,
Feng Wang
Affiliations
Veronica Jové
Centers for Therapeutic Innovation, Pfizer, New York City, NY 10016, USA
Heather Wheeler
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Chiachin Wilson Lee
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
David R. Healy
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Kymberly Levine
Centers for Therapeutic Innovation, Pfizer, New York City, NY 10016, USA
Erik C. Ralph
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Masaya Yamaguchi
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Ziyue Karen Jiang
Comparative Medicine, Pfizer, La Jolla, CA 92121, USA
Edward Cabral
Comparative Medicine, Pfizer, La Jolla, CA 92121, USA
Yingrong Xu
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Jeffrey Stock
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Bing Yang
Comparative Medicine, Pfizer, La Jolla, CA 92121, USA
Anand Giddabasappa
Comparative Medicine, Pfizer, La Jolla, CA 92121, USA
Paula Loria
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Agustin Casimiro-Garcia
Medicine Design, Pfizer, Cambridge, MA 02139, USA
Benedikt M. Kessler
Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
Adán Pinto-Fernández
Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
Véronique Frattini
Centers for Therapeutic Innovation, Pfizer, New York City, NY 10016, USA
Paul D. Wes
Centers for Therapeutic Innovation, Pfizer, New York City, NY 10016, USA; Corresponding author
Feng Wang
Discovery Sciences, Medicine Design, Pfizer, Groton, CT 06340, USA
Summary: Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. Type I interferon signaling is negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, and inhibits Type I interferon receptor activity through its scaffold role. USP18 loss-of-function dramatically impacts immune regulation, pathogen susceptibility, and tumor growth. However, prior studies have reached conflicting conclusions regarding the relative importance of catalytic versus scaffold function. Here, we develop biochemical and cellular methods to systematically define the physiological role of USP18. By comparing a patient-derived mutation impairing scaffold function (I60N) to a mutation disrupting catalytic activity (C64S), we demonstrate that scaffold function is critical for cancer cell vulnerability to Type I interferon. Surprisingly, we discovered that human USP18 exhibits minimal catalytic activity, in stark contrast to mouse USP18. These findings resolve human USP18's mechanism-of-action and enable USP18-targeted therapeutics.