IRF2 degradation tunes the innate immune response

Cristhian Cadena; Rohit Reja; Emma Bolech; Joshua D. Webster; Vasumathi Kameswaran; Marco Claudio De Simone; Cynthia Chen; Jian Wei Jiang; Kathy Hötzel; Kamela O. Alegre; Zhenyu Tan; Raymond Newland; Ryan L. Kelly; Spyros Darmanis; Bence Dániel; Ishan Deshpande; Kim Newton; Nobuhiko Kayagaki; Vishva M. Dixit

doi:10.1101/2025.09.23.678148

ImmunologybioRxivSep 23, 2025

Preprint

IRF2 degradation tunes the innate immune response

Cristhian Cadena iD, Rohit Reja iD, Emma Bolech iD, Joshua D. Webster iD, Vasumathi Kameswaran iD, Marco Claudio De Simone iD, Cynthia Chen iD, Jian Wei Jiang iD, Kathy Hötzel iD, Kamela O. Alegre iD, Zhenyu Tan, Raymond Newland, Ryan L. Kelly iD, Spyros Darmanis iD, Bence Dániel iD, Ishan Deshpande iD, Kim Newton iD, Nobuhiko Kayagaki iD, Vishva M. Dixit iD

Abstract

The transcription factor IRF2 protects against skin inflammation in mice and humans but, paradoxically, promotes pyroptosis by inducing Gsdmd. How IRF2 activates some proinflammatory genes, but suppresses others is unclear. We show that skin inflammation in Irf2-deficient mice is driven by IRF1 activation of interferon-stimulated genes (ISGs). Chromatin profiling revealed that IRF1 and IRF2 occupy the same ISG regulatory sites, but as a weaker transcriptional activator, IRF2 limited ISG transcription by IRF1. Toll-like receptor signaling favored IRF1-driven transcription by inducing Irf1. In addition, IRF1 recruited the ubiquitin ligase SPOP to ISG sites, resulting in proteasomal degradation of IRF2. This shift from IRF2 to IRF1 occupancy enhanced ISG transcription. Collectively, these findings define a hierarchical transcriptional circuit in which IRF2 limits IRF1 activity under homeostatic conditions but is displaced during an immune response, allowing IRF1-dependent gene programs central to innate immunity and autoinflammation.

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