Transmembrane Protein 135 (TMEM135) is a Liver X Receptor Target Gene that Mediates an Auxiliary Peroxisome Matrix Protein Import Pathway

The liver x receptors (LXRs) are key regulators of systemic lipid metabolism. We identified transmembrane protein 135 (TMEM135), a peroxisomal protein with an unknown function, as a novel LXR target gene. The LXRs directly induce TMEM135 transcription in humans via an LXR response element in the 5-prime untranslated region, but do not increase Tmem135 in murine cells. Functionally, knockdown of TMEM135 in vitro and in vivo results in many features typical of peroxisomal disorders such as steatosis and reduced peroxisomal β-oxidation. Mechanistically, proteomic and Western blot analyses indicated that TMEM135 mediates import of peroxisome matrix proteins necessary for β-oxidation and bile acid synthesis. These findings indicate that TMEM135 is an LXR-inducible regulator of peroxisome catabolic and anabolic processes by mediating an auxiliary matrix protein import pathway, and thus may represent a novel therapeutic target for disorders associated with peroxisome dysfunction.