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UNC93B1 curbs cytosolic DNA signaling by promoting STING degradation |
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| Authors: | Zhenliang He Sichao Ye Yifan Xing Yaming Jiu Jin Zhong |
| Institution: | 1. Unit of Viral Hepatitis, Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences, Shanghai, China
University of Chinese Academy of Sciences, Beijing, China Equal contribution;2. Unit of Viral Hepatitis, Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences, Shanghai, China University of Chinese Academy of Sciences, Beijing, China;3. Unit of Cell Biology and Imaging Study of Pathogen Host Interaction, Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences, Shanghai, China University of Chinese Academy of Sciences, Beijing, China;4. Unit of Viral Hepatitis, Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences, Shanghai, China |
| Abstract: | UNC93B1 is a trafficking chaperone of endosomal Toll-like receptors (TLRs) and plays an essential role in the TLR-mediated innate signaling. However, whether it is also involved in other innate immune sensing or cellular pathways remains largely unexplored. Here we investigated the role of UNC93B1 in cytosolic DNA-triggered cGAS-STING signaling in mouse and human cell lines. We showed that while UNC93B1 deficiency blunts the signal transduction by TLR3, it augments innate immune responses to cytosolic DNA stimulation and DNA virus infection. Mechanistic study reveals a distinct action of UNC93B1 upon STING, but not other parts along the cGAS-STING-TBK1 axis, through regulating the protein level of STING at both resting and cytosolic DNA-stimulated conditions. UNC93B1 can directly interact and traffic along with STING, and the disruption of this interaction causes accumulation of STING that subsequently leads to augmented signaling responses upon its activation. These findings reveal a new function of UNC93B1 in negatively regulating STING-mediated signaling responses. |
| Keywords: | DNA sensing innate immunity STING TLR UNC93B1 |