Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death
Rosalind L. Ang, Mark Chan, Diana Legarda, John P. Sundberg, Shao‐Cong Sun, Virginia Gillespie, Nicholas Chun, Peter S. Heeger, Huabao Xiong, Sérgio A. Lira, Adrian T. Ting
Abstract
Significance The mechanisms underlying inflammatory disorders are poorly understood. In this study, we show that inappropriate cell death may cause uncontrolled inflammation. We found that CYLD, an enzyme that removes K63-linked polyubiquitination, is normally inhibited. But in the cpdm mouse strain that has a loss-of-function in the Sharpin gene, the brake on CYLD is no longer present. When CYLD is no longer inhibited, it turns on death signaling in cells exposed to the cytokine TNF, and the ensuing inappropriate cell death causes skin inflammation and other immune disorders in the cpdm mouse. Removing CYLD from the cpdm mouse prevents cell death and reverses the inflammation. We conclude that excessive CYLD activity leads to inappropriate cell death and inflammation.