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Endoplasmic reticulum (ER) stress occurs when protein folding or maturation is disrupted. A malfunction in the ER stress response can lead to cell death and has been observed in many neurological diseases. However, how the ER stress response is regulated in neuronal cells remains largely unclear. Here, we studied an E3 ubiquitin ligase named neural precursor cell expressed developmentally down‐regulated protein 4‐like (Nedd4‐2). Nedd4‐2 is highly expressed in the brain and has a high affinity toward ubiquitinating membrane‐bound proteins. We first utilized unbiased proteomic profiling with ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) of isolated membrane fractions from mouse whole brains to identify novel targets of Nedd4‐2. Through this screen, we found that the expression and ubiquitination of ribosomal proteins are regulated by Nedd4‐2 and we confirmed an association between Nedd4‐2 and ribosomes through ribosome sedimentation and polysome profiling. Further, we utilized immunoprecipitation and western blotting to show that induction of ER stress promotes an association between Nedd4‐2 and ribosomal proteins, which is mediated through dephosphorylation of Nedd4‐2 at serine‐342. This increased interaction between Nedd4‐2 and ribosomal proteins in turn mediates ER stress‐associated translational suppression. In summary, the results of this study demonstrate a novel regulatory mechanism underlying the ER stress response and a novel function of Nedd4‐2 in translational control. Our findings may shed light on neurological diseases in which the ER stress response or the function of Nedd4‐2 is dysregulated. [ABSTRACT FROM AUTHOR]