NFE2L1 is an endoplasmic reticulum membrane sensor which, in response to various stresses, it is released from the ER membrane following cleavage by the protease DDI2 and translocates into the nucleus to form the transcription factor NRF1 []. In conditions of excess cholesterol, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, this allows the expression of genes promoting cholesterol removal []. In response to oxidative stress, Nrf1 up-regulates expression of antioxidant genes by binding to the antioxidant response elements (AREs) present in the promoter of these genes []. In humans Nrf1 exists in two forms, p120 and p110. p120 is embedded in the ER membrane, while p110 is soluble and can enter the nucleus [, ].
