Updated project metadata. RNA splicing and the ubiquitin system allow the functional proteome to adapt in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here we show that the deregulation of the spliceosome B complex caused by USP39 deficiency leads to a novel splicing profile characterized by the use of cryptic 5′splice sites. Importantly, disruptive variants evade mRNA surveillance pathways and are translated into topologically incorrect proteins. These cryptic isoforms disrupt proteostasis and activate the unfolded protein response, causing ER stress-induced cell death. Human cells respond to this proteotoxicity by enhancing ubiquitin-mediated proteolysis and ER-phagy. Our findings show how cell death triggered by cryptic splicing can be mitigated, and provide insight into the molecular pathogenesis of diseases such as retinitis pigmentosa.