title: Rhomboid domain-containing protein 3 is a negative regulator of TLR3-triggered natural killer cell activation.
abstract: Rhomboid domain-containing protein 3 (Rhbdd3), which belongs to a family of proteins with rhomboid domain, is widely expressed in immune cells; however, the roles of the Rhbdd members, including Rhbdd3, in immunity remain unknown. Natural killer (NK) cells are critical for host immune defense and also can mediate inflammatory diseases such as hepatitis. Although much is known about how NK cells are activated, the detailed mechanisms for negative regulation of NK cell activation remain to be fully understood. Using Rhbdd3-deficient mice, we reveal that Rhbdd3, selectively up-regulated in NK cells upon Toll-like receptor 3 (TLR3) stimulation, negatively regulates TLR3-mediated NK cell activation in a feedback manner. Rhbdd3 inhibits TLR3-triggered IFN-γ and granzyme B expression of NK cells in cell-cell contact dependence of accessory cells such as dendritic cells and Kupffer cells. Rhbdd3 interacts with DNAX activation protein of 12 kDa and promotes its degradation, inhibiting MAPK activation in TLR3-triggered NK cells. Furthermore, Rhbdd3 plays a critical role in attenuating TLR3-triggered acute inflammation by controlling NK cell activation and accumulation in liver and disrupting NK cell-Kupffer cell interaction. Therefore, Rhbdd3 is a feedback inhibitor of TLR3-triggered NK cell activation. Our study outlines a mechanism for the negative regulation of NK cell activation and also provides clues for the function of the rhomboid proteins in immunity.
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Shuxun
authors.initials: S
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.forename: Sheng
authors.initials: S
authors.lastname: Xu
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Bao
authors.forename: Minghong
authors.initials: M
authors.lastname: Jiang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002450:Cell Communication; D003713:Dendritic Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D007694:Killer Cells, Natural / Q000378:metabolism*; D007728:Kupffer Cells / Q000166:cytology; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011070:Poly I-C / Q000378:metabolism; D034622:RNA Interference; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C582250:RHBDD3 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C
keywords: immune regulation; innate immunity; poly(I:C)