Protein quality control is a continuous process in which a protein`s folding status is constantly monitored. Mislocalized proteins are processed by the various quality control pathways, as they are seldom misfolded due to inappropriate cellular surroundings. Polypeptides that fail to translocate into the ER due to an inefficient signal peptide, mutations or ER stress are recognized by the pre-emptive ER associated quality control (pQC) pathway and degraded by the 26S proteasome. In this presentation we demonstrate the physiological role of the pQC in maintaining ER homeostasis by regulating ER translocation. Impairment in the pQC pathway induced in RNF149 knockout mice leads to hyper-translocation and subsequent development of ER stress. We will present our data from RNF149 conditional beta-cell knockout mice, demonstrating the diabetic phenotype of these mice in several diabetic scenarios. Keeping in mind that certain maturity-onset diabetes of the young (MODY) patients in which a mutation within the INS gene (R6C) affect Insulin ER translocation driving Insulin to become a pQC substrate, imply that regulating insulin translocation maybe useful as a therapeutic target in certain cases of Diabetes.