UNC13D inhibits STING signaling by attenuating its oligomerization on the endoplasmic reticulum

Article20 September 2022 Source DataTransparent process UNC13D inhibits STING signaling by attenuating its oligomerization on the endoplasmic reticulum Pu Song Corresponding Author Pu Song [email protected] orcid.org/0000-0001-8314-4736 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: Conceptualization, Data curation, Formal analysis, Validation, ​Investigation, Visualization, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Weiwei Yang Weiwei Yang Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: Validation, ​Investigation Search for more papers by this author Karen F Lou Karen F Lou Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Hao Dong Hao Dong Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Heng Zhang Heng Zhang Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Beiming Wang Beiming Wang Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Danying Chen Corresponding Author Danying Chen [email protected] orcid.org/0000-0002-2826-3449 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: Conceptualization, Supervision, Funding acquisition, Visualization, Methodology, Project administration, Writing - review & editing Search for more papers by this author Pu Song Corresponding Author Pu Song [email protected] orcid.org/0000-0001-8314-4736 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: Conceptualization, Data curation, Formal analysis, Validation, ​Investigation, Visualization, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Weiwei Yang Weiwei Yang Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: Validation, ​Investigation Search for more papers by this author Karen F Lou Karen F Lou Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Hao Dong Hao Dong Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Heng Zhang Heng Zhang Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Beiming Wang Beiming Wang Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: ​Investigation Search for more papers by this author Danying Chen Corresponding Author Danying Chen [email protected] orcid.org/0000-0002-2826-3449 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China Contribution: Conceptualization, Supervision, Funding acquisition, Visualization, Methodology, Project administration, Writing - review & editing Search for more papers by this author Author Information Pu Song *,1, Weiwei Yang1, Karen F Lou1, Hao Dong1, Heng Zhang1, Beiming Wang1 and Danying Chen *,1 1Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China *Corresponding author. Tel: +86 18310596618; E-mail: [email protected] *Corresponding author. Tel: +86 13552129455; E-mail: [email protected] EMBO Reports (2022)23:e55099https://doi.org/10.15252/embr.202255099 Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Stimulator of interferon genes (STING) is an essential signaling protein that is located on the endoplasmic reticulum (ER) and triggers the production of type I interferons (IFN) and proinflammatory cytokines in response to pathogenic DNA. Aberrant activation of STING is linked to autoimmune diseases. The mechanisms underlying homeostatic regulation of STING are unclear. Here, we report that UNC13D, which is associated with familial hemophagocytic lymphohistiocytosis (FHL3), is a negative regulator of the STING-mediated innate immune response. UNC13D colocalizes with STING on the ER and inhibits STING oligomerization. Cellular knockdown and knockout of UNC13D promote the production of interferon-β (IFN-β) induced by DNA viruses, but not RNA viruses. Moreover, UNC13D deficiency also increases the basal level of proinflammatory cytokines. These effects are diminished by an inhibitor of STING signaling. Furthermore, the domains involved in the UNC13D/STING interaction on both proteins are mapped. Our findings provide insight into the regulatory mechanism of STING, the previously unknown cellular function of UNC13D and the potential pathogenesis of FHL3. Synopsis STING signaling is essential for the production of type I interferons and proinflammatory cytokines in response to pathogenic DNA. UNC13D, which is associated with familial hemophagocytic lymphohistiocytosis, is a negative regulator of STING-mediated innate immune responses. UNC13D colocalizes and directly interacts with STING on the endoplasmic reticulum and inhibits STING oligomerization. Depletion of UNC13D promote the production of interferon-β induced by DNA viruses, but not RNA viruses. UNC13D deficiency increases the basal level of proinflammatory cytokines. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 23,Issue 11,07 November 2022This month's cover highlights the article Human‐specific ARHGAP11B ensures human‐like basal progenitor levels in hominid cerebral organoids by Jan Fischer, Eduardo Fernández Ortuño, Fabio Marsoner, Michael Heide and colleagues. The cover illustrates that ectopic expression of human ARHGAP11B in chimpanzee cerebral organoids (blue +ARHGAP11B mirror) leads to increased basal progenitor levels � one hallmark of neocortex expansion (blue chimpanzee brain). Loss of ARHGAP11B or inhibition of ARHGAP11B�s function in human cerebral organoids (magenta -ARHGAP11B mirror) leads to reduced basal progenitor levels � indicative for a reduced neocortex size (magenta human brain). (Cover concept by the authors. Cover illustration by DrawImpacts (https://www.drawimpacts.com.) Volume 23Issue 117 November 2022In this issue RelatedDetailsLoading ...