title: Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation.
abstract: TREX1 is an endoplasmic reticulum (ER)-associated negative regulator of innate immunity. TREX1 mutations are associated with autoimmune and autoinflammatory diseases. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to accumulate, but it is unknown how dominant frameshift (fs) mutations that encode DNase-active but mislocalized proteins cause disease. We found that the TREX1 C terminus suppressed immune activation by interacting with the ER oligosaccharyltransferase (OST) complex and stabilizing its catalytic integrity. C-terminal truncation of TREX1 by fs mutations dysregulated the OST complex, leading to free glycan release from dolichol carriers, as well as immune activation and autoantibody production. A connection between OST dysregulation and immune disorders was demonstrated in Trex1(-/-) mice, TREX1-V235fs patient lymphoblasts, and TREX1-V235fs knock-in mice. Inhibiting OST with aclacinomycin corrects the glycan and immune defects associated with Trex1 deficiency or fs mutation. This function of the TREX1 C terminus suggests a potential therapeutic option for TREX1-fs mutant-associated diseases.
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Maroof
authors: M
authors: Hasan
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Charles S
authors: CS
authors: Fermaintt
authors: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Ningguo
authors: N
authors: Gao
authors: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors: Tomomi
authors: T
authors: Sakai
authors: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors: Takuya
authors: T
authors: Miyazaki
authors: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Sixin
authors: S
authors: Jiang
authors: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Quan-Zhen
authors: QZ
authors: Li
authors: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: John P
authors: JP
authors: Atkinson
authors: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors: Herbert C
authors: HC
authors: Morse
authors: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: mark.lehrman@utsouthwestern.edu.
authors: Mark A
authors: MA
authors: Lehrman
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: nan.yan@utsouthwestern.edu.
authors: Nan
authors: N
authors: Yan
mesh_terms: D015250:Aclarubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology*; D004622:Embryo, Mammalian / Q000166:cytology; D005090:Exodeoxyribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016368:Frameshift Mutation; D057809:HEK293 Cells; D006367:HeLa Cells; D006602:Hexosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015151:Immunoblotting; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D008565:Membrane Proteins; D010750:Phosphoproteins; D011134:Polysaccharides; C011157:aclacinomycins; D015250:Aclarubicin; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1