UNC93B1 curbs cytosolic DNA signaling by promoting STING degradation.
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.
['He|Zhenliang|Z|', 'Ye|Sichao|S|', 'Xing|Yifan|Y|', 'Jiu|Yaming|Y|', 'Zhong|Jin|J|0000-0002-3554-1275']
D000818:Animals D002460:Cell Line D003600:Cytosol D004247:DNA D011992:Endosomes D057809:HEK293 Cells D006801:Humans D007113:Immunity, Innate D008565:Membrane Proteins D026901:Membrane Transport Proteins D051379:Mice D008810:Mice, Inbred C57BL D015398:Signal Transduction D000074084:THP-1 Cells
UNC93B1 STING TLR innate immunity DNA sensing