Mitotic Phosphorylation of TREX1 C Terminus Disrupts TREX1 Regulation of the Oligosaccharyltransferase Complex

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. [Display omitted] •During mitosis, TREX1 is predominately phosphorylated at Serine-261 by Cyclin B/CDK1•Mitotic phosphorylation does not affect TREX1 DNase activity•Mitotic phosphorylation disrupts TREX1 interaction with the OST subunit RPN1•Disrupting TREX1 phosphorylation at Serine-261 elevates a glycol-gene signature TREX1 has a DNase-independent function in the C terminus that regulates the ER oligosaccharyltransferase (OST) activity. Kucej et al. found that TREX1 is phosphorylated during mitosis at Serine-261 in the C terminus. Mitotic phosphorylation disrupts TREX1 interaction with the OST complex without affecting its DNase activity.