Proteostasis at the ER entry point: quality control mechanisms safeguarding protein biogenesis from targeting to translocation

Abstract The endoplasmic reticulum (ER) serves as the primary entry point through which secretory and membrane proteins access the endomembrane system. Maintaining the fidelity of protein biogenesis requires stringent quality control mechanisms that safeguard protein targeting, localization, membrane insertion, translocation, and subsequent folding. Failures at any of these steps can compromise cellular proteostasis. Recent studies have revealed that the ER entry point is protected by a multilayered quality control network operating before, during, and immediately after engagement with the ER membrane. These pathways monitor protein targeting, regulate protein influx, resolve failures in membrane insertion and translocation, and maintain the integrity of ribosome–translocon complexes during cotranslational translocation. Together, they eliminate aberrant intermediates, preserve translocation capacity, and coordinate protein entry with the folding and degradative capacity of the ER under physiological and stress conditions. Although many of these surveillance pathways converge on the Sec61 translocon, proteostasis at the ER entry point extends beyond the translocon itself to safeguard protein biogenesis at the cytosol–ER interface. In this Review, we discuss the emerging principles of quality control that safeguard protein biogenesis from targeting to translocation and examine how these mechanisms interface with the unfolded protein response (UPR) and ER-phagy to maintain ER proteostasis. We propose proteostasis at the ER entry point as a unifying framework for understanding how diverse quality control mechanisms are integrated, thereby preserving the fidelity of protein biogenesis and the capacity for efficient protein entry into the ER.