The ER localization domain consists of a hydrophilic linker region of unknown function [although this region harbors many SLE mutations (Crow and Rehwinkel, 2009)] and a small hydrophobic segment at the extreme carboxyl-terminus that sorts TREX1 to the cytosolic leaflet of the ER membrane by serving as an ER tail-anchor (rather than a classical transmembrane span; Lee-Kirsch et al., 2007; Lindahl et al., 2009). Here, TREX1 is linked to systemic lupus erythematosus.