title: Negative regulation of RIG-I-mediated innate antiviral signaling by SEC14L1.
abstract: Retinoic acid-inducible gene I (RIG-I) is a key sensor for recognizing nucleic acids derived from RNA viruses and triggers beta interferon (IFN-β) production. Because of its important role in antiviral innate immunity, the activity of RIG-I must be tightly controlled. Here, we used yeast two-hybrid screening to identify a SEC14 family member, SEC14L1, as a RIG-I-associated negative regulator. Transfected SEC14L1 interacted with RIG-I, and endogenous SEC14L1 associated with RIG-I in a viral infection-inducible manner. Overexpression of SEC14L1 inhibited transcriptional activity of the IFN-β promoter induced by RIG-I but not TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Knockdown of endogenous SEC14L1 in both HEK293T cells and HT1080 cells potentiated RIG-I and Sendai virus-triggered IFN-β production as well as attenuated the replication of Newcastle disease virus. SEC14L1 interacted with the N-terminal domain of RIG-I (RIG-I caspase activation and recruitment domain [RIG-I-CARD]) and competed with VISA/MAVS/IPS-1/Cardif for RIG-I-CARD binding. Domain mapping further indicated that the PRELI-MSF1 and CRAL-TRIO domains but not the GOLD domain of SEC14L1 are required for interaction and inhibitory function. These findings suggest that SEC14L1 functions as a novel negative regulator of RIG-I-mediated antiviral signaling by preventing RIG-I interaction with the downstream effector.
authors.affiliation: The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Meng-Tong
authors.initials: MT
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Di
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Yang
authors.forename: Hai-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: Fei-Xiong
authors.initials: FX
authors.lastname: Zhang
authors.forename: Zhong-He
authors.initials: ZH
authors.lastname: Zhai
authors.forename: Dan-Ying
authors.initials: DY
authors.lastname: Chen
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D009522:Newcastle disease virus / Q000276:immunology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012367:RNA, Viral / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000276:immunology*; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; D012367:RNA, Viral; D011971:Receptors, Immunologic; C100642:SEC14L1 protein, human; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases