Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation

Maroof Hasan, Charles S. Fermaintt, Ningguo Gao, Tomomi Sakai, Takuya Miyazaki, Sixin Jiang, Quan Zhen Li, John P. Atkinson, Herbert C. Morse, Mark A. Lehrman, Nan Yan

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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.

Original languageEnglish
Article number3143
Pages (from-to)463-474
Number of pages12
JournalImmunity
Volume43
Issue number3
DOIs
StatePublished - Sep 15 2015

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    Hasan, M., Fermaintt, C. S., Gao, N., Sakai, T., Miyazaki, T., Jiang, S., Li, Q. Z., Atkinson, J. P., Morse, H. C., Lehrman, M. A., & Yan, N. (2015). Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation. Immunity, 43(3), 463-474. [3143]. https://doi.org/10.1016/j.immuni.2015.07.022