title: Mitotic Phosphorylation of TREX1 C Terminus Disrupts TREX1 Regulation of the Oligosaccharyltransferase Complex.
abstract: TREX1 mutations are associated with several autoimmune and inflammatory diseases. The N-terminal DNase domain of TREX1 is important for preventing self-DNA from activating the interferon response. The C terminus of TREX1 is required for ER localization and regulation of oligosacchariyltransferase (OST) activity. Here, we show that during mitosis TREX1 is predominately phosphorylated at the C-terminal Serine-261 by Cyclin B/CDK1. TREX1 is dephosphorylated quickly at mitotic exit, likely by PP1/PP2-type serine/threonine phosphatase. Mitotic phosphorylation does not affect TREX1 DNase activity. Phosphomimetic mutations of mitotic phosphorylation sites in TREX1 disrupted the interaction with the OST subunit RPN1. RNA-seq analysis of Trex1-/-mouse embryonic fibroblasts expressing TREX1 wild-type or phosphor-mutants revealed a glycol-gene signature that is elevated when TREX1 mitotic phosphorylation sites are disrupted. Thus, the cell-cycle-dependent post-translation modification of TREX1 regulates its interaction with OST, which may have important implications for immune disease associated with the DNase-independent function of TREX1.
authors.affiliation: Departments of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kucej
authors.affiliation: Departments of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fermaintt
authors.affiliation: Departments of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Departments of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Irizarry-Caro
authors.affiliation: Departments of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: nan.yan@utsouthwestern.edu.
authors.forename: Nan
authors.initials: N
authors.lastname: Yan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000737:chemistry* / Q000378:metabolism; D006018:Glycols / Q000378:metabolism; D006367:HeLa Cells; D006602:Hexosyltransferases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008938:Mitosis; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D013329:Structure-Activity Relationship; D059467:Transcriptome / Q000235:genetics
chemical_list: D019926:Cyclin B; D006018:Glycols; D008565:Membrane Proteins; D010750:Phosphoproteins; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase; D016203:CDC2 Protein Kinase; D003851:Deoxyribonucleases; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1
keywords: DNase; TREX1; autoimmune disease; cell cycle